This invention relates to dipeptide compounds which are growth hormone secretagogues and are useful for the treatment and prevention of osteoporosis.
Growth hormone (GH), which is secreted from the pituitary gland, stimulates growth of all tissues of the body that are capable of growing. In addition, growth hormone is known to have the following basic effects on the metabolic process of the body:
1. Increased rate of protein synthesis in substantially all cells of the body;
2. Decreased rate of carbohydrate utilization in cells of the body;
3. Increased mobilization of free fatty acids and use of fatty acids for energy.
Deficiency in growth hormone results in a variety of medical disorders. In children, it causes dwarfism. In adults, the consequences of acquired GH deficiency include profound reduction in lean body mass and concomitant increase in total body fat, particularly in the truncal region. Decreased skeletal and cardiac muscle mass and muscle strength lead to, a significant reduction in exercise capacity. Bone density is also reduced. Administration of exogenous growth hormone has been shown to reverse many of the metabolic changes. Additional benefits of therapy have included reduction in LDL cholesterol and improved psychological well-being.
In cases where increased levels of growth hormone were desired, the problem was generally solved by providing exogenous growth hormone or by administering an agent which stimulated growth hormone production and/or release. In either case the peptidyl nature of the compound necessitated that it be administered by injection. Initially the source of growth hormone was the extraction of the pituitary glands of cadavers. This resulted in an expensive product, and carried with it the risk that a disease associated with the source of the pituitary gland could be transmitted to the recipient of the growth hormone (e.g., Jacob-Creutzfeld disease). Recently, recombinant growth hormone has become available which, while no longer carrying any risk of disease transmission, is still a very expensive product which must be given by injection or by a nasal spray.
Most GH deficiencies are caused by defects in GH release, not primary defects in pituitary synthesis of GH. Therefore, an alternative strategy for normalizing serum GH levels is by stimulating its release from somatotrophs. Increasing GH secretion can be achieved by stimulating or inhibiting various neurotransmitter systems in the brain and hypothalamus. As a result, the development of synthetic growth hormone-releasing agents to stimulate pituitary GH secretion are being pursued, and may have several advantages over expensive and inconvenient GH replacement therapy. By acting along physiologic regulatory pathways, the most desirable agents would stimulate pulsatile GH secretion, and excessive levels of GH that have been associated with the undesirable side effects of exogenous GH administration would be avoided by virtue of intact negative feedback loops.
Physiologic and pharmacologic stimulators of GH secretion include arginine, L-3,4-dihydroxyphenylalanine (L-DOPA), glucagon, vasopressin, and insulin induced hypoglycemia, as well as activities such as sleep and exercise, indirectly cause growth hormone to be released from the pituitary by acting in some fashion on the hypothalamus perhaps either to decrease somatostatin secretion or to increase the secretion of the known secretagogue growth hormone releasing factor (GHRF) or an unknown endogenous growth hormone-releasing hormone or all of these.
Other compounds have been developed which stimulate the release of endogenous growth hormone such as analogous peptidyl compounds related to GRF or the peptides of U.S. Pat. No. 4,411,890. These peptides, while considerably smaller than growth hormones are still susceptible to various proteases. As with most peptides, their potential for oral bioavailability is low. WO 94/13696 refers to certain spiropiperidines and homologues which promote release of growth hormone. Preferred compounds are of the general structure shown below. 
WO 94/11012 refers to certain dipeptides that promote release of growth hormone. These dipeptides have the general structure 
The compounds of WO 94/11012 and WO 94/13696 are reported to be useful in the treatment of osteoporosis in combination with parathyroid hormone or a bisphosphonate.
This invention provides compounds of the formula: 
the racemic-diastereomeric mixtures and optical isomers of said compounds and the pharmaceutically-acceptable salts and prodrugs thereof,
wherein
e is 0 or 1;
n and w are each independently 0, 1 or 2, provided that w and n cannot both be 0 at the same time;
Y is oxygen or sulfur;
R1 is hydrogen, xe2x80x94CN, xe2x80x94(CH2)qN(X6)C(O)X6, xe2x80x94(CH2)qN(X6)C(O)(CH2)txe2x80x94A1, xe2x80x94(CH2)qN(X6)SO2xe2x80x94(CH2)txe2x80x94A1, xe2x80x94(CH2)qN(X6)SO2X6, xe2x80x94(CH2)qN(X6)C(O)N(X6)(CH2)txe2x80x94A1, xe2x80x94(CH2)qN(X6)C(O)N(X6)(X6), xe2x80x94(CH2)qC(O)N(X6)(X6), xe2x80x94(CH2)qC(O)N(X6)(CH2)txe2x80x94A1, xe2x80x94(CH2)qC(O)OX6, xe2x80x94(CH2)qC(O)O(CH2)txe2x80x94A1, xe2x80x94(CH2)qOX6, xe2x80x94(CH2)qOC(O)X6, xe2x80x94(CH2)qOC(O)(CH2)txe2x80x94A1, xe2x80x94(CH2)qOC(O)N(X6)(CH2)txe2x80x94A1, xe2x80x94(CH2)qOC(O)N(X6)(X6), xe2x80x94(CH2)qC(O)X6, xe2x80x94CH2)qC(O)(CH2)txe2x80x94A1, xe2x80x94(CH2)qN(X6)C(O)OX6, xe2x80x94(CH2)qN(X6)SO2N(X6)(X6), xe2x80x94(CH2)qS(O)mX6, xe2x80x94(CH2)qS(O)m(CH2)txe2x80x94A1, xe2x80x94(C1-C10)alkyl, xe2x80x94(CH2)txe2x80x94A1, xe2x80x94(CH2)qxe2x80x94(C3-C7)cycloalkyl, xe2x80x94(CH2)qxe2x80x94Y1xe2x80x94(C1-C6)alkyl, xe2x80x94(CH2)qxe2x80x94Y1xe2x80x94(CH2)txe2x80x94A1 or xe2x80x94(CH2)qxe2x80x94Y1xe2x80x94(CH2)txe2x80x94(C3-C7)cycloalkyl;
where the alkyl and cycloalkyl groups in the definition of R1 are optionally substituted with (C1-C4)alkyl, hydroxyl, (C1-C4)alkoxy, carboxyl, xe2x80x94CONH2, xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94CO2(C1-C4)alkyl ester, 1 H-tetrazol-5-yl or 1, 2 or 3 fluoro;
Y1 is O, S(O)m, xe2x80x94C(O)NX6xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x95x90Cxe2x80x94, xe2x80x94N(X6)C(O)xe2x80x94, xe2x80x94C(O)N)X6xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94OC(O)N(X6)xe2x80x94or xe2x80x94OC(O)xe2x80x94;
q is 0, 1, 2, 3 or4;
t is 0, 1, 2 or 3;
said (CH2)q group and (CH2)t group may each be optionally substituted with hydroxyl, (C1-C4)alkoxy, carboxyl, xe2x80x94CONH2, xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94CO2(C1-C4)alkyl ester, 1H-tetrazol-5-yl, 1, 2 or 3 fluoro, or 1 or 2 (C1-C4)alkyl;
R2 is hydrogen, (C1-C8)alkyl, xe2x80x94(C0-C3)alkyl-(C3-C8)cycloalkyl, xe2x80x94(C1-C4)alkyl-A1 or A1; where the alkyl groups and the cycloalkyl groups in the definition of R2 are optionally substituted with hydroxyl, xe2x80x94C(O)OX6, xe2x80x94C(O)N(X6)(X6), xe2x80x94N(X6)(X6), xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94C(O)A1, xe2x80x94C(O)(X6), CF3, CN or 1, 2 or 3 halogen;
R3 is A1, (C1-C10)alkyl, xe2x80x94(C1-C6)alkyl-A1, xe2x80x94(C1-C6)alkyl-(C3-C7)cycloalkyl, xe2x80x94(C1-C5)alkyl-X1xe2x80x94(C1-C5)alkyl, xe2x80x94(C1-C5)alkyl-X1xe2x80x94(C0-C5)alkyl-A1 or xe2x80x94(C1 -C5)alkyl-X1xe2x80x94(C1-C5)alkyl-(C3-C7)cycloalkyl;
where the alkyl groups in the definition of R3 are optionally substituted with, xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94C(O)OX3, 1, 2, 3, 4 or 5 halogens, or 1, 2 or 3 OX3;
X1 is O, S(O)m, xe2x80x94N(X2)C(O)xe2x80x94, xe2x80x94C(O)N(X2)xe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, CX2xe2x95x90CX2xe2x80x94, xe2x80x94N(X2)C(O)Oxe2x80x94, xe2x80x94OC(O)N(X2)xe2x80x94or xe2x80x94Cxe2x89xa1Cxe2x80x94;
R4 is hydrogen, (C1-C6)alkyl or (C3-C7)cycloalkyl, or R4 is taken together with R3 and the carbon atom to which they are attached and form (C5-C7)cycloalkyl, (C5-C7)cycloalkenyl, a partially saturated or fully saturated 4- to 8-membered ring having 1 to 4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen, or is a bicyclic ring system consisting of a partially saturated or fully saturated 5- or 6-membered ring, fused to a partially saturated, fully unsaturated or fully saturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen;
X4 is hydrogen or (C1-C6)alkyl or X4 is taken together with R4 and the nitrogen atom to which X4 is attached and the carbon atom to which R4 is attached and form a five to seven membered ring;
R6 is a bond or is 
where a and b are independently 0, 1, 2 or 3;
X5 and X5a are each independently selected from the group consisting of hydrogen, trifluoromethyl, A1 and optionally substituted (C1-C6)alkyl;
the optionally substituted (C1-C6)alkyl in the definition of X5 and X5a is optionally substituted with a substituent selected from the group consisting of A1, OX2, xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94C(O)OX2, (C3-C7)cycloalkyl, xe2x80x94N(X2)(X2) and xe2x80x94C(O)N(X2)(X2);
or the carbon bearing X5 or X5a forms one or two alkylene bridges with the nitrogen atom bearing R7 and R8 wherein each alkylene bridge contains 1 to 5 carbon atoms, provided that when one alkylene bridge is formed then X5 or X5a but not both may be on the carbon atom and R7 or R8 but not both may be on the nitrogen atom and further provided that when two alkylene bridges are formed then X5 and X5a cannot be on the carbon atom and R7 and R8 cannot be on the nitrogen atom;
or X5 is taken together with X5a and the carbon atom to which they are attached and form a partially saturated or fully saturated 3- to 7-membered ring, or a partially saturated or fully saturated 4- to 8-membered ring having 1 to 4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen;
or X5 is taken together with X5a and the carbon atom to which they are attached and form a bicyclic ring system consisting of a partially saturated or fully saturated 5- or 6-membered ring, optionally having 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen, fused to a partially saturated, fully saturated or fully unsaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen;
Z1 is a bond, O or Nxe2x80x94X2, provided that when a and b are both 0 then Z1 is not Nxe2x80x94X2 or O;
R7 and R8 are independently hydrogen or optionally substituted (C1-C6)alkyl; where the optionally substituted (C1-C6)alkyl in the definition of R7 and R8 is optionally independently substituted with A1, xe2x80x94C(O)Oxe2x80x94(C1-C6)alkyl, xe2x80x94S(O)m(C1-C6)alkyl, 1 to 5 halogens, 1 to 3 hydroxy, 1 to 3 xe2x80x94Oxe2x80x94C(O)(C1-C10)alkyl or 1 to 3 (C1-C6)alkoxy; or
R7 and R8 can be taken together to form xe2x80x94(CH2)rxe2x80x94Lxe2x80x94(CH2)rxe2x80x94;
where L is C(X2)(X2), S(O)m or N(X2);
A1 for each occurrence is independently (C5-C7)cycloalkenyt, phenyl or a partially saturated, fully saturated or fully unsaturated 4- to 8-membered ring optionally having 1 to 4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen, a bicyclic ring system consisting of a partially saturated, fully unsaturated or fully saturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen, fused to a partially saturated, fully saturated or fully unsaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen;
A1 for each occurrence is independently optionally substituted, in one or optionally both rings if A1 is a bicyclic ring system, with up to three substituents, each substituent independently selected from the group consisting of F, Cl, Br, I, OCF3, OCF2H, CF3, CH3, OCH3, xe2x80x94OX6, xe2x80x94C(O)N(X6)(X6), xe2x80x94C(O)OX6, oxo, (C1-C6)alkyl, nitro, cyano, benzyl, xe2x80x94S(O)m(C1-C6)alkyl, 1H-tetrazol-5-yl, phenyl, phenoxy, phenylalkyloxy, halophenyl, methylenedioxy, xe2x80x94N(X6)(X6), xe2x80x94N(X6)C(O)(X6), xe2x80x94SO2N(X6)(X6), xe2x80x94N(X6)SO2-phenyl, xe2x80x94N(X6)SO2X6, xe2x80x94CONX11X12, xe2x80x94SO2NX11X12, xe2x80x94NX6SO2X12, xe2x80x94NX6CONX11X12, xe2x80x94NX6SO2NX11X12, xe2x80x94NX6C(O)X12, imidazolyl, thiazolyl or tetrazolyl, provided that if A1 is optionally substituted with methylenedioxy then it can only be substituted with one methylenedioxy;
where X11 is hydrogen or optionally substituted (C1-C6)alkyl;
the optionally substituted (C1-C6)alkyl defined for X11 is optionally independently substituted with phenyl, phenoxy, (C1-C6)alkoxycarbonyl, xe2x80x94S(O)m(C1-C6)alkyl 1 to 5 halogens, 1 to 3 hydroxy, 1 to 3 (C1-C10)alkanoyloxy or 1 to 3 (C1-C6)alkoxy;
X12 is hydrogen, (C1-C6)alkyl, phenyl, thiazolyl, imidazolyl, furyl or thienyl, provided that when X12 is not hydrogen, X12 is optionally substituted with one to three substituents independently selected from the group consisting of Cl, F, CH3, OCH3, OCF3 and CF3;
or X11and X12 are taken together to form xe2x80x94(CH2)rxe2x80x94L1xe2x80x94(CH2)rxe2x80x94;
L1 is C(X2)(X2), O, S(O)m or N(X2);
r for each occurrence is independently 1, 2 or 3;
X2 for each occurrence is independently hydrogen, optionally substituted (C1-C6)alkyl, or optionally substituted (C3-C7)cycloalkyl, where the optionally substituted (C1-C6)alkyl and optionally substituted (C3-C7)cycloalkyl in the definition of X2 are optionally independently substituted with xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94C(O)OX3, 1 to 5 halogens or 1 to 3 OX3;
X3 for each occurrence is independently hydrogen or (C1-C6)alkyl;
X6 is independently hydrogen, optionally substituted (C1-C6)alkyl, (C2-C6)halogenated alkyl, optionally substituted (C3-C7)cydoalkyl, (C3-C7)xe2x80x94halogenatedcycloalkyl, where optionally substituted (C1-C6)alkyl and optionally substituted (C3-C7)cycloalkyl in the definition of X6 is optionally independently substituted by 1 or 2 (C1-C4)alkyl, hydroxyl, (C1-C4)alkoxy, carboxyl, CONH2, xe2x80x94S(O)m(C1C6)alkyl, carboxylate (C1-C4)alkyl ester, or 1H-tetrazol-5-yl; or
when there are two X6 groups on one atom and both X6 are independently (C1-C6)alkyl, the two (C1-C6)alkyl groups may be optionally joined and, together with the atom to which the two X6 groups are attached, form a 4- to 9-membered ring optionally having oxygen, sulfur or NX7;
X7 is hydrogen or (C1-C6)alkyl optionally substituted with hydroxyl; and
m for each occurrence is independently 0, 1 or 2; with the proviso that:
X6 and X12 cannot be hydrogen when it is attached to C(O) or S2 in the form C(O)X6, C(O)X12, SO2X6 or SO2X12; and
when R6 is a bond then L is N(X2) and each r in the definition xe2x80x94(CH2)rxe2x80x94Lxe2x80x94(CH2)rxe2x80x94 is independently 2 or 3.
A preferred group of compounds, designated the xe2x80x9cA Groupxe2x80x9d, contains those compounds having the formula I as shown hereinabove wherein X4 is hydrogen; R4 is hydrogen or methyl; R7 is hydrogen or (C1C3)alkyl; R8 is hydrogen or (C1-C3)alkyl optionally substituted with one or two hydroxyl groups;
R6 is 
where Z1 is a bond and a is 0 or 1;
X5 and X5a are each independently hydrogen, trifluoromethyl, phenyl, optionally substituted (C1-C6)alkyl;
where the optionally substituted (C1-C6)alkyl is optionally substituted with OX2, imidazolyl, phenyl, indolyl, p-hydroxyphenyl, (C5-C7)cycloalkyl, xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94N(X2)(X2) or xe2x80x94C(O)N(X2)(X2);
or X5 and R7 are taken together to form a (C1-C5)alkylene bridge, and the other substituents not defined for the xe2x80x9cA Groupxe2x80x9d compounds are as defined for formula (I) hereinabove.
A group of compounds, which is preferred among the xe2x80x9cA Groupxe2x80x9d of compounds, designated the xe2x80x9cB Groupxe2x80x9d, contains those compounds of the xe2x80x9cA Groupxe2x80x9d, having the formula I as shown hereinabove, wherein b is 0; X5 and X5a are each independently hydrogen, (C1-C3)alkyl or hydroxy(C1-C3)alkyl; R3 is selected from the group consisting of 1-indolyl-CH2xe2x80x94, 2-indolyl-C2xe2x80x94, 3-indolyl-CH2xe2x80x94, 1-naphthyl-CH2xe2x80x94, 2-naphthyl-CH2xe2x80x94, 1-benzimidazolyl-CH2xe2x80x94, 2-benzimidazolyl-CH2xe2x80x94, phenyl-(C1-C4)alkylxe2x80x94, 2-pyridyl-(C1-C4)alkylxe2x80x94, 3-pyridyl-(C1-C4)alkylxe2x80x94, 4-pyridyl-(C1-C4)alkylxe2x80x94, phenyl-CH2xe2x80x94Sxe2x80x94CH2xe2x80x94, thienyl-(C1-C4)alkylxe2x80x94, phenyl-(C0-C3)alkyl-Oxe2x80x94CH2xe2x80x94, phenyl-CH2xe2x80x94Oxe2x80x94phenyl-CH2xe2x80x94, and 3-benzothienyl-CH2xe2x80x94;
where the aryl portion(s) of the groups defined for R3 are optionally substituted with one to three substituents, each substituent being independently selected from the group consisting of methylenedioxy, F, Cl, CH3, OCH3, OCF3, OCF2H and CF3.
A group of compounds, which is preferred among the xe2x80x9cB Groupxe2x80x9d of compounds, designated the xe2x80x9cC Groupxe2x80x9d, contain those compounds of the xe2x80x9cB Groupxe2x80x9d, having the formula I as shown hereinabove, wherein R4 is hydrogen; a is 0; n is 1 or 2; w is 0 or 1; X5 and X5a are each independently, hydrogen, methyl or hydroxymethyl, provided that when X5 is hydrogen then X5a is not hydrogen;
R7 and R8 are each hydrogen; and
R3 is phenyl-CH2xe2x80x94Oxe2x80x94CH2xe2x80x94, phenyl-CH2xe2x80x94Sxe2x80x94CH2xe2x80x94, 1-naphthyl-CH2xe2x80x94, 2-naphthyl-CH2xe2x80x94, phenyl-(CH2)3xe2x80x94 or 3indolyl-CH2xe2x80x94;
where the aryl portion of the groups defined for R3 is optionally substituted with one to three substituents, each substituent being independently selected from the group consisting of fluoro, chloro, methyl, OCH3, OCF2H, OCF3 and CF3.
A group of compounds, which is preferred among the xe2x80x9cC Groupxe2x80x9d of compounds, designated the xe2x80x9cD Groupxe2x80x9d, contains those compounds of the xe2x80x9cC Groupxe2x80x9d, having the formula I as shown hereinabove, wherein R1 is xe2x80x94(CH2)txe2x80x94A1, xe2x80x94(CH2)qxe2x80x94(C3-C7)cycloalkyl or (C1-C10)alkyl;
where A1 in the definition of R1 is optionally substituted with one to three substituents, each substituent being independently selected from the group consisting of fluoro, chloro, methyl, OCH3, OCF2H, OCF3 and CF3;
the cycloalkyl and alkyl groups in the definition of R1 are optionally substituted with (C1-C4)alkyl, hydroxyl, (C1-C4)alkoxy, carboxyl, CONH2, xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94CO2(C1C4)alkyl ester, 1H-tetrazol-5yl or 1 to 3 fluoro;
Y is O; R2 is hydrogen, xe2x80x94(C0-C3)alkylxe2x80x94(C3-C8)cycloalkyl, phenyl or (C1-C8)alkyl where the (C1-C8)alkyl group is optionally substituted with hydroxyl, xe2x80x94CF3 or 1 to 3 halogen.
A group of compounds, which is preferred among the xe2x80x9cD Groupxe2x80x9d of compounds, designated the xe2x80x9cE Groupxe2x80x9d, contains those compounds of the xe2x80x9cD Groupxe2x80x9d wherein w is 0 and n is 1.
Another group of compounds, which is preferred among the xe2x80x9cD Groupxe2x80x9d of compounds, designated the xe2x80x9cF Groupxe2x80x9d, are those compounds of the xe2x80x9cD Groupxe2x80x9d, having the formula I as shown hereinabove, wherein e is 0; n and w are each 1;
R1 is xe2x80x94(CH2)txe2x80x94A1;
where A1 in the definition of R1 is phenyl, thienyl, thiazolyl, pyridyl or pyrimidyl which is optionally substituted with one to three substituents, each substituent being independently selected from the group consisting of F, Cl, Me, OMe, CF3, OCF3 and OCF2H;
t is 0, 1 or 2;
and R3 is phenylxe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94, phenyl-(CH2)3xe2x80x94 or 3-indolylxe2x80x94CH2xe2x80x94, where the aryl portion is optionally substituted with one to three substituents, each substituent being independently selected from the group consisting of F, Cl, Me, OMe, CF3, OCF3 or OCF2H.
A group of compounds, which is preferred among the xe2x80x9cF Groupxe2x80x9d of compounds, designated the xe2x80x9cG Groupxe2x80x9d, contains those compounds of the xe2x80x9cF Groupxe2x80x9d, having the formula I as shown hereinabove, wherein X5 and X5a are each methyl; R1 is xe2x80x94CH2-phenyl, xe2x80x94CH2-4-fluoro-phenyl, xe2x80x94CH2-pyridyl or xe2x80x94CH2-thiazolyl and R2 is hydrogen, methyl, ethyl, t-butyl or xe2x80x94CH2CF3.
A group of compounds, which is preferred among the xe2x80x9cG Groupxe2x80x9d of compounds, designated the xe2x80x9cG1 Groupxe2x80x9d, contains those compounds of the xe2x80x9cG Groupxe2x80x9d, and have the formula 
the racemic-diastereomeric mixtures and optical isomers of said compounds wherein
R1 is xe2x80x94CH2-phenyl, R2 is methyl and R3 is xe2x80x94(CH2)3-phenyl;
R1 is xe2x80x94CH2-phenyl, R2 is methyl and R3is 3-indolyl-CH2xe2x80x94;
R1 is xe2x80x94CH2-phenyl, R2 is ethyl and R3is 3-indolyl-CH2xe2x80x94;
R1 is xe2x80x94CH2-4-fluoro-phenyl, R2 is methyl and R3 is 3-indolyl-CH2xe2x80x94;
R1 is xe2x80x94CH2-phenyl, R2 is methyl and R3 is xe2x80x94CH2xe2x80x94Oxe2x80x94CH2-phenyl;
R1 is xe2x80x94CH2-phenyl, R2 is ethyl and R3 is xe2x80x94CH2xe2x80x94Oxe2x80x94CH2-phenyl;
R1 is xe2x80x94CH2-phenyl, R2 is xe2x80x94CH2xe2x80x94CF3 and R3 is xe2x80x94CH2xe2x80x94Oxe2x80x94CH2-phenyl;
R1 is xe2x80x94CH2-4-fluoro-phenyl, R2 is methyl and R3 is xe2x80x94CH2xe2x80x94Oxe2x80x94CH2-phenyl;
R1 is xe2x80x94CH2-phenyl, R2 is t-butyl and R3 is xe2x80x94CH2xe2x80x94Oxe2x80x94CH2-phenyl; or
R1 is xe2x80x94CH2-phenyl, R2 is methyl and R3 is xe2x80x94CH2xe2x80x94Oxe2x80x94CH2-3,4di-fluoro-phenyl.
The diastereomeric mixture of 2-amino-N-[2-(3a-(R,S)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5yl)-1-(R)-(3,4-difluoro-benzyl-oxymethyl)-2-oxo-ethyl]-2-methyl-propionamide is preferred among the xe2x80x9cG1 Groupxe2x80x9d of compounds and the separated 3a-(R) and 3a-(S) isomers are preferred of the diastereomeric mixture.
A group of compounds, which is preferred among the xe2x80x9cG Groupxe2x80x9d of compounds, designated the xe2x80x9cH Groupxe2x80x9d, contains those compounds of the xe2x80x9cG Groupxe2x80x9d, having the formula I as shown hereinabove, wherein R1 is xe2x80x94CH2-phenyl and R3 is phenyl-(CH2)3xe2x80x94.
The diastereomeric mixture of 2-amino-N-[1-(3a-(R,S)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridine-5carbonyl)4-phenyl-(R)-butyl]-isobutyramide is preferred among the xe2x80x9cH Groupxe2x80x9d of compounds and the separated 3a-(R) and 3a-(S) isomers are preferred of the diastereomeric mixture.
A group of compounds, which is preferred among the xe2x80x9cG Groupxe2x80x9d of compounds, designated the xe2x80x9cI Groupxe2x80x9d, contains those compounds of the xe2x80x9cG Groupxe2x80x9d wherein R1 is xe2x80x94CH2-phenyl or xe2x80x94CH2-4-fluoro-phenyl and R3 is 3-indolyl-CH2xe2x80x94.
The diastereomeric mixture of 2-amino-N-[2-(3a-(R,S)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5yl)-1-(R)-(1H-indol-3-ylmethyl)-2-oxoethyl]-isobutyramide is preferred among the xe2x80x9cI Groupxe2x80x9d of compounds and the separated 3a-(R) and 3a-(S) isomers are preferred of the diastereomeric mixture.
The diastereomeric mixture of 2-amino-N-[2-(3a-(R,S)-benzyl-2-ethyl3oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-(1H-indol3-ylmethyl)2-oxo-ethyl]-isobutyramide is also preferred among the xe2x80x9cI Groupxe2x80x9d of compounds and the separated 3a-(R) and 3a-(S) isomers are preferred of the diastereomeric mixture.
The diastereomeric mixture of 2-amino-N-[2-[3a-(R,S)-(4-fluoro-benzyl)-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3c]pyridin-5-yl-]-1-(R)-(1H-indol-ylmethyl)-2-oxo-ethyl]-isobutyramide is also preferred among the xe2x80x9cI Groupxe2x80x9d of compounds and the separated 3a-(R) and 3a-(S) isomers are preferred of the diastereomeric mixture.
A group of compounds which is preferred among the xe2x80x9cG Groupxe2x80x9d of compounds, designated the xe2x80x9cJ Groupxe2x80x9d, contains those compounds of the xe2x80x9cG Groupxe2x80x9d wherein R1 is xe2x80x94CH2-phenyl or xe2x80x94CH2-4-fluoro-phenyl and R3 is phenyl-CH2xe2x80x94Oxe2x80x94CH2xe2x80x94.
The diastereomeric mixture of 2-amino-N-[2-(3a-(R,S)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide is preferred among the xe2x80x9cJ Groupxe2x80x9d of compounds, the separated 3a-(R) and 3a-(S) isomers are preferred of the diastereomeric mixture, the 3a-(R) isomer is preferred over the 3a-(S) isomer, and the L-tartaric acid salt of the 3a-(R) isomer is a preferred salt.
The diastereomeric mixture of 2-amino-N-[2-(3a-(R,S)-benzyl-2-ethyl3oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide is also preferred among the xe2x80x9cJ Groupxe2x80x9d of compounds and the separated 3a-(R) and 3a-(S) isomers are preferred of the diastereomeric mixture.
The diastereomeric mixture of 2-amino-N-{2-[3a-(R,S)-benzyl-3-oxo-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7hexahydropyrazolo[4,3-c]pyridin-5yl]-1-(R)-benzyloxymethyl-2-oxo-ethyl}-isobutyramide is also preferred among the xe2x80x9cJ Groupxe2x80x9d of compounds, the separated 3a-(R) and 3a-(S) isomers are preferred of the diastereomeric mixture and the 3a-(R) isomer is preferred over the 3a-(S) isomer.
The diastereomeric mixture of 2-amino-N-{1-(R)-benzyloxymethyl-2-[3a-(R,S)-(4-fluoro-benzyl)-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-2-oxo-ethyl}-isobutyramide is also preferred among the xe2x80x9cJ Groupxe2x80x9d of compounds and the separated 3a-(R) and 3a-(S) isomers are preferred of the diastereomeric mixture.
The diastereomeric mixture of 2-amino-N-[2-(3a-(R,S)-benzyl-2-tert-butyl3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyrdin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide is also preferred among the xe2x80x9cJ Groupxe2x80x9d of compounds and the separated 3a-(R) and 3a-(S) isomers are preferred of the diastereomeric mixture.
A group of compounds which is preferred among the xe2x80x9cD Groupxe2x80x9d of compounds, designated the xe2x80x9cK Groupxe2x80x9d, contains those compounds of the xe2x80x9cD Groupxe2x80x9d wherein e is 1; n is 1; w is 1; R1 is xe2x80x94(CH2)txe2x80x94A1;
where A1 in the definition of R1 is phenyl, thienyl, thiazolyl, pyridyl or pyrimidyl which is optionally substituted with one to three substituents, each substituent being independently selected from the group consisting of F, Cl, Me, OMe, CF3, OCF3 and OCF2H;
t is 0, 1 or 2;
and R3 is phenyl-CH2xe2x80x94Oxe2x80x94CH2xe2x80x94, phenyl-(CH2)3- or 3-indolyl-CH2-, where the aryl portion is optionally substituted with one to three substituents, each substituent being independently selected from the group consisting of F, Cl, Me, OMe, CF3, OCF3 or OCF2H.
A group of compounds which is preferred among the xe2x80x9cK Groupxe2x80x9d of compounds, designated the xe2x80x9cL Groupxe2x80x9d, are those compounds of the xe2x80x9cK Groupxe2x80x9d wherein X5 and X5a are each methyl; R1 is xe2x80x94CH2-phenyl, xe2x80x94CH2-4fluoro-phenyl, xe2x80x94CH2-pyridyl or xe2x80x94CH2-thiazolyl and R2 is hydrogen, methyl, ethyl, t-butyl or xe2x80x94CH2CF3.
A group of compounds which is preferred among the xe2x80x9cL Groupxe2x80x9d, designated the xe2x80x9cL1 Groupxe2x80x9d, are those compounds of the xe2x80x9cL Groupxe2x80x9d wherein R1 is xe2x80x94CH2-phenyl; R2 is hydrogen or methyl and R3 is xe2x80x94CH2xe2x80x94CH2-phenyl.
The diastereomeric mixture of 2-amino-N-[2-(3a-(R,S)-benzyl-3oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide is preferred among the xe2x80x9cJ Groupxe2x80x9d, the separated 3a-(R) and 3a-(S) isomers are preferred of the diastereomeric mixture and the 3a-(R) isomer is preferred over the 3a-(S) isomer.
Another group of compounds, which is preferred among the xe2x80x9cA Groupxe2x80x9d of compounds, designated the xe2x80x9cM Groupxe2x80x9d, contains those compounds of the xe2x80x9cA Groupxe2x80x9d, having the formula I as shown hereinabove, wherein b is 0; X5 and X5a are each independently hydrogen, (C1-C3)alkyl or hydroxy(C1-C3)alkyl;
R3 is selected from the group consisting of 1-indolyl-CH2xe2x80x94, 2-indolyl-CH2xe2x80x94, 3-indolyl-CH2xe2x80x94, 1-naphthyl-CH2xe2x80x94, 2-naphthyl-CH2xe2x80x94, 1-benzimidazolyl-CH2xe2x80x94, 2-benzimidazolyl-CH2xe2x80x94, phenyl-(C1-C4)alkylxe2x80x94, 2-pyridyl-(C1-C4)alkylxe2x80x94, 3-pyridyl-(C1-C4)alkylxe2x80x94, 4-pyridyl-(C1-C4)alkylxe2x80x94, phenyl-CH2xe2x80x94Sxe2x80x94CH2xe2x80x94, thienyl-(C1-C4)alkylxe2x80x94, phenyl-(C0-C3)alkylxe2x80x94Oxe2x80x94CH2xe2x80x94, phenyl-CH2xe2x80x94Oxe2x80x94phenyl-CH2xe2x80x94, 3-benzothienyl-CH2xe2x80x94, thienyl-CH2xe2x80x94Oxe2x80x94CH2xe2x80x94, thiazolyl-CH2xe2x80x94Oxe2x80x94CH2xe2x80x94, pyridyl-CH2xe2x80x94Oxe2x80x94CH2xe2x80x94, pyrimidyl-CH2xe2x80x94Oxe2x80x94CH2xe2x80x94 and phenyl-xe2x80x94Oxe2x80x94CH2xe2x80x94CH2;
where the aryl portion(s) of the groups defined for R3 are optionally substituted with one to three substituents, each substituent being independently selected from the group consisting of methylenedioxy, F, Cl, CH3, OCH3, OCF3, OCF2H and CF3.
A group of compounds, which is preferred among the xe2x80x9cM Groupxe2x80x9d of compounds, designated the xe2x80x9cM1 Groupxe2x80x9d, contains those compounds of the xe2x80x9cM Groupxe2x80x9d, having the formula I as shown hereinabove, wherein R4 is hydrogen; a is 0; n is 1; w is 1; e is 0; X5 and X5a are each independently, hydrogen, methyl or hydroxymethyl, provided that when X5 is hydrogen then X5a is not hydrogen; R7 and R8 are each hydrogen; Y is oxygen; R2 is hydrogen, methyl, ethyl, propyl, i-propyl, t-butyl, xe2x80x94CH2CF3, CF3 or xe2x80x94CH2-cyclopropyl; R1 is CH2xe2x80x94A1; where A1 in the definition of R1 is phenyl, thienyl, thiazolyl, pyridyl or pyrimidyl which is optionally substituted with one to three substituents, each substituent being independently selected from the group consisting of F, Cl, Me, OMe, CF3, OCF3 and OCF2H; and R3 is phenyl-CH2xe2x80x94Oxe2x80x94CH2xe2x80x94, phenyl-CH2)3xe2x80x94, 3-indolyl-CH2xe2x80x94, thienyl-C2xe2x80x94Oxe2x80x94CH2xe2x80x94, thiazolyl-CH2xe2x80x94Oxe2x80x94CH2xe2x80x94, pyridyl-CH2xe2x80x94Oxe2x80x94CH2xe2x80x94, pyrimidyl-CH2xe2x80x94Oxe2x80x94CH2xe2x80x94 or phenylxe2x80x94Oxe2x80x94CH2xe2x80x94CH2, where the aryl portion is optionally substituted with one to three substituents, each substituent being independently selected from the group consisting of F, Cl, Me, OMe, CF3, OCF3 and OCF2H.
A group of compounds, which is preferred among the xe2x80x9cM1 Groupxe2x80x9d of compounds, designated the xe2x80x9cN Groupxe2x80x9d, contains those compounds of the xe2x80x9cM1 Groupxe2x80x9d, having the formula I as shown hereinabove, wherein X5 and X5a are each methyl; R2 is methyl, ethyl, or xe2x80x94CH2CF3; A1 is phenyl optionally substituted with one to three substituents, each substituent being independently selected from the group consisting of F, Cl, Me, OMe, CF3, OCF3 and OCF2H; R3 is phenyl-CH2xe2x80x94Oxe2x80x94CH2xe2x80x94, phenyl-(CH2)3xe2x80x94 or thienyl-CH2xe2x80x94Oxe2x80x94CH2xe2x80x94 where the aryl portion is optionally substituted with one to three substituents, each substituent being independently selected from the group consisting of F, Cl, Me, OMe, CF3, OCF3 and OCF2H.
Another group of compounds, which is preferred among the xe2x80x9cM1 Groupxe2x80x9d of compounds, designated the xe2x80x9cO Groupxe2x80x9d, contains those compounds of the xe2x80x9cM1 Groupxe2x80x9d, having the formula I as shown hereinabove, wherein X5 and X5a are each methyl; R2 is methyl, ethyl, or CH2CF3; A1 is 2-pyridyl or 3-pyridyl optionally substituted with one to two substituents, each substituent being independently selected from the group consisting of F, Cl, Me, OMe, CF3, OCF3 and OCF2H; R3 is phenyl-CH2xe2x80x94Oxe2x80x94CH2xe2x80x94, phenyl-(CH2)3xe2x80x94 or thienyl-CH2xe2x80x94CH2xe2x80x94 where the aryl portion is optionally substituted with one to three substituents, each substituent being independently selected from the group consisting of F, Cl, Me, OMe, CF3, OCF3 and OCF2H.
Another group of compounds, which is preferred among the xe2x80x9cM1 Groupxe2x80x9d of compounds, designated the xe2x80x9cP Groupxe2x80x9d, contains those compounds of the xe2x80x9cM1 Groupxe2x80x9d, having the formula I as shown hereinabove, wherein X5 and X5a are each methyl; R2 is methyl, ethyl, or CH2CF3; A1 is phenyl optionally substituted with one to three substituents, each substituent being independently selected from the group consisting of F, Cl, Me, OMe, CF3, OCF3 and OCF2H; R3 is 2-pyridyl-CH2xe2x80x94Oxe2x80x94CH2xe2x80x94, or 3pyridyl-CH2xe2x80x94CH2xe2x80x94 where the aryl portion is optionally substituted with one to two substituents, each substituent being independently selected from the group consisting of F, Cl, Me, OMe, CF3, OCF3 and OCF2H.
A group of compounds, which is preferred among the xe2x80x9cO Groupxe2x80x9d of compounds, designated the xe2x80x9cQ Groupxe2x80x9d, contains those compounds of the xe2x80x9cO Groupxe2x80x9d, having the formula 
the racemic-diastereomeric mixtures and optical isomers of said compounds wherein
R2 is methyl; A1 is 2-pyridyl; and R3 is xe2x80x94CH2xe2x80x94Oxe2x80x94CH2-phenyl;
R2 is CH2CF3; A1 is 2-pyridyl; and R3 is xe2x80x94CH2xe2x80x94Oxe2x80x94CH2-3-chloro-phenyl;
R2 is CH2CF3; A1 is 2-pyridyl; and R3 is xe2x80x94CH2xe2x80x94Oxe2x80x94CH2-4-chloro-phenyl;
R2 is CH2CF3; A1 is 2-pyridyl; and R3 is xe2x80x94CH2xe2x80x94Oxe2x80x94CH2-2,4-di-chloro-phenyl;
R2 is CH2CF3; A1 is 2-pyridyl; and R3 is xe2x80x94CH2xe2x80x94Oxe2x80x94CH2-3-chloro-thiophene; or
R2 is CH2CF3; A1 is 2-pyridyl; and R3 is xe2x80x94CH2xe2x80x94Oxe2x80x94CH2-2,4-di-fluoro-phenyl.
The diastereomeric mixture of 2-amino-N-[1-(R)-benzyloxymethyl-2-(2-methyl-3-oxo-3a-(R,S)pyridin-2-ylmethyl-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethyl]-2-methyl-propionamide is preferred among the xe2x80x9cQ Groupxe2x80x9d of compounds and the separated 3a-(R) and 3a-(S) isomers are preferred of the diastereomeric mixture.
The diastereomeric mixture of 2-amino-N-{1-(R)-(3-chloro-benzyloxy-methyl)-2-oxo-2-[3-oxo-3a-(R,S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5yl]-ethyl}-2-methyl-propionamide is preferred among the xe2x80x9cQ Groupxe2x80x9d of compounds and the separated 3a-(R) and 3a-(S) isomers are preferred of the diastereomeric mixture.
The diastereomeric mixture of 2-amino-N-{1-(R)-(4-chloro-benzyloxy-methyl)-2-oxo-2-[3-oxo-3a-(R,S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)2,3,3a, 4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethyl}-2-methyl-propionamide is preferred among the xe2x80x9cQ Groupxe2x80x9d of compounds and the separated 3a-(R) and 3a-(S) isomers are preferred of the diastereomeric mixture.
The diastereomeric mixture of 2-amino-N-{1-(R)-(2,4-dichloro-benzyloxymnethyl)2-oxo-2-[3-oxo-3a-(R,S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydropyrazolo[4,3-c]pyridin5-yl]-ethyl)}-2-methyl-propionamide is preferred among the xe2x80x9cQ Groupxe2x80x9d of compounds and the separated 3a-(R) and 3a-(S) isomers are preferred of the diastereomeric mixture.
The diastereomeric mixture of 2-amino-N-{1-(R)-(4-chloro-thiophen-2-ylmethoxymethyl)-2-oxo-2-[3oxo-3a-(R,S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,5,7-hexahydro-pyrazolo[3,4-c]pyridin-6-yl]-ethyl}-2-methyl-propionamide is preferred among the xe2x80x9cQ Groupxe2x80x9d of compounds and the separated 3a-(R) and 3a-(S) isomers are preferred of the diastereomeric mixture.
The diastereomeric mixture of 2-amino-N-{1-(R)-(2,4-difluoro-benzyloxy-methyl) -2-oxo-2-[3-oxo-3a-(R,S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethyl}-2-methyl-propionamide is preferred among the xe2x80x9cQ Groupxe2x80x9d of compounds and the separated 3a-(R) and 3a-(S) isomers are preferred of the diastereomeric mixture.
A group of compounds which contains intermediates useful in synthesizing the compounds of formula (I) are of the formula 
the racemic-diastereomeric mixtures and optical isomers of said compounds and the pharmaceutically-acceptable salts thereof, wherein e is 0 or 1; n and w are each independently 0, 1 or 2, provided that w and n cannot both be 0 at the same time;
R1 is hydrogen, xe2x80x94CN, xe2x80x94CH2)qN(X6)C(O)X6, xe2x80x94(CH2)qN(X6)C(O)(CH2)txe2x80x94A1, xe2x80x94(CH2)qN(X6)SO2(CH2)txe2x80x94A1, xe2x80x94(CH2)qN(X6)SO2X6, xe2x80x94(CH2)qN(X6)C(O)N(X6)(CH2)txe2x80x94A1, xe2x80x94(CH2)qN(X6)C(O)N(X6)(X6), xe2x80x94(CH2)qC(O)N(X6)(X6), xe2x80x94(CH2)qC(O)N(X6)(CH2)txe2x80x94A1, xe2x80x94(CH2)qC(O)OX6, xe2x80x94(CH2)qC(O)O(CH2)txe2x80x94A1, xe2x80x94CH2)qOX6, xe2x80x94(CH2)qOC(O)X6, xe2x80x94(CH2)qOC(O)(CH2)txe2x80x94A1, xe2x80x94(CH2)qOC(O)N(X6)(CH2)txe2x80x94A1, xe2x80x94(CH2)qOC(O)N(X6)(X6), xe2x80x94(CH2)qC(O)X6, xe2x80x94(CH2)qC(O)(CH2)txe2x80x94A1, xe2x80x94(CH2)qN(X6)C(O)OX6, xe2x80x94(CH2)qN(X6)SO2N(X6)(X6), xe2x80x94(CH2)qS(O)mX6, xe2x80x94(CH2)qS(O)m(CH2)txe2x80x94A1, xe2x80x94(C1-C10)alkyl, xe2x80x94CH2)txe2x80x94A1, xe2x80x94(CH2)qxe2x80x94(C3-C7)cycoalkyl, xe2x80x94(CH2)qxe2x80x94Y1xe2x80x94(C1-C6)alkyl, xe2x80x94(CH2)qxe2x80x94Y1xe2x80x94(CH2)txe2x80x94A1 or xe2x80x94(CH2)qxe2x80x94Y1xe2x80x94(CH2)txe2x80x94(C3-C7)cycloalkyl;
where the alkyl and cycloalkyl groups in the definition of R1 are optionally substituted with (C1-C4)alkyl, hydroxyl, (C1-C4)alkoxy, carboxyl, CONH2, xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94CO2(C1-C4)alkyl, 1H-tetrazol-5-yl or 1 to 3 fluoro; Y1 is O, S(O)m, xe2x80x94C(O)NX6, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94N(X6)C(O)xe2x80x94, xe2x80x94C(O)NX6xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94OC(O)N(X6)xe2x80x94 or xe2x80x94OC(O)xe2x80x94; q is 0, 1, 2, 3 or 4; t is 0, 1, 2 or 3;
said (CH2)q group and (CH2)t group may each be optionally substituted with 1 to 3 fluoro, 1 or 2 (C1-C4)alkyl, hydroxyl, (C1-C4)alkoxy, carboxyl, xe2x80x94CONH2,
xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94CO2(C1-C4)alkyl ester, or 1H-tetrazol-5-yl;
R2 is hydrogen, (C1-C8)alkyl, xe2x80x94(C0-C3)alkyl-(C3-C8)cycloalkyl, xe2x80x94(C1-C4)alkyl-A1 or A1;
where the alkyl groups and the cycloalkyl groups in the definition of R2 are optionally substituted by hydroxyl, xe2x80x94C(O)OX6, xe2x80x94C(O)N(X6)(X6), xe2x80x94N(X6)(X6), xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94C(O)A1, xe2x80x94C(O)(X6), CF3, CN or 1 to 3 halogen;
A1 for each occurrence is independently (C5-C7)cycloalkenyl, phenyl or a partially saturated, fully saturated or fully unsaturated 4- to 8-membered ring optionally having 1 to 4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen, or a bicyclic ring system consisting of a partially saturated, fully unsaturated or fully saturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen, fused to a partially saturated, fully saturated or fully unsaturated 5- or 6-membered ring, optionally having 1 to -4 -heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen;
A1 for each occurrence is independently optionally substituted, in one or optionally both rings if A1 is a bicyclic ring system, with up to three substituents, each substituent independently selected from the group consisting of F, Cl, Br, I, OCF3, OCF2H, CF3, CH3, OCH3, xe2x80x94OX6, xe2x80x94C(O)N(X6)(X6), xe2x80x94C(O)OX6, oxo, (C1-C6)alkyl, nitro, cyano, benzyl, xe2x80x94S(O)m(C1-C6)alkyl, 1H-tetrazol-5-yl, phenyl, phenoxy, phenylalkyloxy, halophenyl, methylenedioxy, xe2x80x94N(X6)(X6), xe2x80x94N(X6)C(O)(X6), xe2x80x94SO2N(X6)(X6), xe2x80x94N(X6)SO2-phenyl, xe2x80x94N(X6)SO2X6, xe2x80x94CONX11X12, xe2x80x94SO2NX11X12, xe2x80x94NX6SO2X12, xe2x80x94NX6CONX11X12, xe2x80x94NX6SO2NX11X12, xe2x80x94NX6C(O)X12, imidazolyl, thiazolyl and tetrazolyl, provided that if A1 is optionally substituted with methylenedioxy then it can only be substituted by one methylenedioxy;
where X11 is hydrogen or optionally substituted (C1-C6)alkyl;
the optionally substituted (C1-C6)alkyl defined for X11 is optionally independently substituted with phenyl, phenoxy, (C1-C6)alkoxycarbonyl, xe2x80x94S(O)m(C1-C6)alkyl, 1 to 5 halogens, 1 to 3 hydroxy, 1 to 3 (C1-C10)alkanoyloxy or 1 to 3 (C1-C6)alkoxy;
X12 is hydrogen, (C1-C6)alkyl, phenyl, thiazolyl, imidazolyl, furyl or thienyl, provided that when X12 is not hydrogen, X12 is optionally substituted with one to three substituents independently selected from the group consisting of Cl, F, CH3, OCH3, OCF3 and CF3;
or X11 and X12 are taken together to form xe2x80x94(CH2)rxe2x80x94L1xe2x80x94(CH2)rxe2x80x94;
L1 is C(X2)(X2), O, S(O)m or N(X2);
r for each occurrence is independently 1, 2 or 3;
X2 for each occurrence is independently hydrogen, optionally substituted (C1-C6)alkyl, or optionally substituted (C3-C7)cycloalkyl, where the optionally substituted (C1-C6)alkyl and optionally substituted (C3-C7)cycloalkyl in the definition of X2 are optionally independently substituted with xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94C(O)OX3, 1 to 5 halogens or 1 to 3 OX3;
X3 for each occurrence is independently hydrogen or (C1-C6)alkyl;
X6 for each occurrence is independently hydrogen, optionally substituted (C1-C6)alkyl, (C2-C6)halogenated alkyl, optionally substituted (C3-C7)cycloalkyl, (C3-C7)-halogenatedcycloalkyl, where optionally substituted (C1-C6)alkyl and optionally substituted (C3-C7)cycloalkyl in the definition of X6 is optionally independently substituted by, hydroxyl, (C1-C4)alkoxy, carboxyl, CONH2, xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94CO2(C1-C4)alkyl, 1H-tetrazol-5-yl or 1 or 2 (C1-C4)alkyl; or
where there are two X6 groups on one atom and both X6 are (C1-C6)alkyl, the two (C1-C6)alkyl groups may be optionally joined and, together with the atom to which the two X6 groups are attached, form a 4- to 9- membered ring optionally having oxygen, sulfur or NX7;
X7 is hydrogen or (C1-C6)alkyl optionally substituted with hydroxyl; and
m for each occurrence is independently 0, 1 or 2;
with the proviso that:
X6 and X12 cannot be hydrogen when it is attached to C(O) or SO2 in the form C(O)X6, C(O)X12, SO2X6 or SO2X12; and
when R2 is hydrogen then R1 is not xe2x80x94CHxe2x95x90CH-phenyl.
A group of intermediate compounds preferred among the foregoing group of formula (II), designated xe2x80x9cGroup AAxe2x80x9d, contains those compounds wherein w is 0 or 1;
n is 1; R1 is hydrogen, xe2x80x94(CH2)qxe2x80x94(C3-C7)cycloalkyl, xe2x80x94(CH2)txe2x80x94A1 or (C1-C10)alkyl where the (C1-C10)alkyl and (C3-C7)cycloalkyl groups are optionally substituted with 1 to 3 fluoro and A1 in the definition of R1 is optionally substituted with 1 to 3 substituents independently selected from the group consisting of F, Cl, Me, methoxy, CF3, OCF3 and OCF2H; R2 is hydrogen, (C1-C8)alkyl, (C0-C3)alkylxe2x80x94(C3-C7)cycloalkyl, phenyl, or (C1-C3)alkyl-phenyl where the alkyl and phenyl groups are optionally substituted with 1 to 3 substituents independently selected from the group consisting of F, CF3, OH and methoxy.
A group of compounds preferred among the xe2x80x9cAA Groupxe2x80x9d compounds, designated xe2x80x9cBB Groupxe2x80x9d, contains those compounds of xe2x80x9cAA Groupxe2x80x9d wherein w is 1; e is 0; R1 is xe2x80x94CH2-pyridyl, xe2x80x94CH2-thiazolyl, or xe2x80x94CH2-phenyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of fluoro and chloro; and R2 is hydrogen, (C1-C4)alkyl or phenyl where the (C1C4)alkyl or phenyl groups in the definition of R2 is optionally substituted with 1 to 3 substiuents independently selected from the group consisting of fluoro, hydroxy or methoxy.
Compounds which are preferred among the xe2x80x9cBB Groupxe2x80x9d compounds is the diastereomeric mixture of a compound wherein R1 is xe2x80x94CH2-phenyl and R2 is methyl or hydrogen; and the separated 3a-(R) and 3a-(S) isomers are preferred of the diastereomeric mixture.
Another group of intermediate compounds which are useful in the synthesis of the compounds of formula (I) have the formula 
the racemic-diastereomeric mixtures and optical isomers of said compounds wherein
Z100 is methyl, BOC, CBZ, CF3C(O)xe2x80x94, FMOC, TROC, trityl, tosyl, CH3C(O)xe2x80x94 or optionally substituted benzyl which optionally substituted with methoxy, dimethoxy or nitro; e is 0 or 1; n and w are each independently 0, 1 or 2, provided that w and n cannot both be 0 at the same time;
R1 is hydrogen, xe2x80x94CN, xe2x80x94(CH2)qN(X6)C(O)X6), xe2x80x94(CH2)qN(X6)C(O)(CH2)txe2x80x94A1, xe2x80x94(CH2)qN(X6)SO2(CH2)txe2x80x94A1, xe2x80x94(CH2)qN(X6) SO2X6, xe2x80x94(CH2)qN(X6)C(O)N(X6)(CH2)txe2x80x94A1, xe2x80x94(CH2)qN(X6)C(O)N(X6)(X6), xe2x80x94(CH2)qC(O)N(X6)(X6), xe2x80x94(CH2)qC(O)N(X6)(CH2)txe2x80x94A1, xe2x80x94(CH2)qC(O)OX6, xe2x80x94(CH2)qC(O)O(CH2)txe2x80x94A1, xe2x80x94(CH2)qOX6, xe2x80x94(CH2)qOC(O)X6, xe2x80x94(CH2)qOC(O)(CH2)txe2x80x94A1 (CH2)qOC(O)N(X6)(CH2)txe2x80x94A1xe2x80x94(CH2)qOC(O)N(X6)(X6), xe2x80x94(CH2)qC(O)X6xe2x80x94(CH2)qC(O)(CH2)txe2x80x94A1, xe2x80x94(CH2)qN(X6)C(O)OX6, xe2x80x94(CH2)qN(X6)SO2N(X6)(X6) xe2x80x94(CH2)qS(O)mX6, xe2x80x94(CH2)qS(O)m(CH2)txe2x80x94A1, xe2x80x94(C1-C10)alkyl, xe2x80x94(CH2)txe2x80x94A1, xe2x80x94(CH2)qxe2x80x94(C3-C7)cycloalkyl, xe2x80x94(CH2)qxe2x80x94Y1xe2x80x94(C1-C6)alkyl, xe2x80x94(CH2)qxe2x80x94Y1xe2x80x94(CH2)txe2x80x94A1 or xe2x80x94(CH2)qxe2x80x94Y1xe2x80x94(CH2)txe2x80x94(C3-C7)cycloalkyl;
where the alkyl and cycloalkyl groups in the definition of R1 are optionally substituted with (C1-C4)alkyl, hydroxyl, (C1-C4)alkoxy, carboxyl, CONH2, xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94CO2(C1-C4)alkyl, 1H-tetrazol-5-yl or 1 to 3 fluoro;
Y1 is O, S(O)m, xe2x80x94C(O)NX6, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94N(X6)C(O), xe2x80x94C(O)NX6, xe2x80x94C(O)O, xe2x80x94OC(O)N(X6) or xe2x80x94OC(O);
q is 0, 1, 2, 3 or 4;
t is 0, 1, 2 or 3;
said (CH2)q group and (CH2)t group may each be optionally substituted with hydroxyl, (C1-C4)alkoxy, carboxyl, xe2x80x94CONH2, xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94CO2(C1-C4)alkyl, 1H-tetrazol-5-yl, 1 to 3 fluoro or 1 or 2 (C1-C4)alkyl;
R2 is hydrogen, (C1-C8)alkyl, xe2x80x94(C0-C3)alkyl-(C3-C8)cycloalkyl, xe2x80x94(C1-C4)alkyl-A1 or A1; where the alkyl groups and the cycloalkyl groups in the definition of R2 are optionally substituted with hydroxyl, xe2x80x94C(O)OX6, xe2x80x94C(O)N(X6)(X6), xe2x80x94N(X6)(X6), xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94C(O)A1, xe2x80x94C(O)(X6), CF3, CN or 1 to 3 halogen;
A1 for each occurrence is independently (C5-C7)cycloalkenyl, phenyl or a partially saturated, fully saturated or fully unsaturated 4- to 8-membered ring optionally having 1 to 4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen, or a bicyclic ring system consisting of a partially saturated, fully unsaturated or fully saturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen, fused to a partially saturated, fully saturated or fully unsaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen;
A1 for each occurrence is independently optionally substituted, in one or optionally both rings if A1 is a bicyclic ring system, with up to three substituents, each substituent independently selected from the group consisting of F, Cl, Br, I, OCF3, OCF2H, CF3, CH3, OCH3, xe2x80x94OX6, xe2x80x94C(O)N(X6)(X6), xe2x80x94C(O)OX6, oxo, (C1-C6)alkyl, nitro, cyano, benzyl, xe2x80x94S(O)m(C1-C6)alkyl, 1H-tetrazol-5-yl, phenyl, phenoxy, phenylalkyloxy, halophenyl, methylenedioxy, xe2x80x94N(X6)(X6), xe2x80x94N(X6)C(O)(X6), xe2x80x94SO2N(X6)(X6), xe2x80x94N(X6)SO2-phenyl, xe2x80x94N(X6)SO2X6, xe2x80x94CONX11X12, xe2x80x94SO2NX11 X12, xe2x80x94NX6SO2X12, xe2x80x94NX6CONX11X12, xe2x80x94NX6SO2NX11X12, xe2x80x94NX6C(O)X12, imidazolyl, thiazolyl and tetrazolyl, provided that if A1 is optionally substituted with methylenedioxy then it can only be substituted with one methylenedioxy;
where X11 is hydrogen or optionally substituted (C1-C6)alkyl;
the optionally substituted (C1-C6)alkyl defined for X11 is optionally independently substituted with phenyl, phenoxy, (C1-C6)alkoxycarbonyl, xe2x80x94S(O)m(C1-C6)alkyl, 1 to 5 halogens, 1 to 3 hydroxy, I to 3 (C1-C10)alkanoyloxy or 1 to 3 (C1-C6)alkoxy;
X12 is hydrogen, (C1-C6)alkyl, phenyl, thiazolyl, imidazolyl, furyl or thienyl, provided that when X12 is not hydrogen, X12 is optionally substituted with one to three substituents independently selected from the group consisting of Cl, F, CH3, OCH3, OCF3 and CF3;
or X11 and X12 are taken together to form xe2x80x94(CH2)rxe2x80x94L1xe2x80x94(CH2)rxe2x80x94;
L1 is C(X2)(X2), OS(O)m or N(X2);
r for each occurrence is independently 1, 2 or 3;
X2 for each occurrence is independently hydrogen, optionally substituted (C1-C6)alkyl, or optionally substituted (C3-C7)cycloalkyl, where the optionally substituted (C1-C6)alkyl and optionally substituted (C3-C7)cycloalkyl in the definition of X2 are optionally independently substituted with xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94C(O)OX3, 1 to 5 halogens or 1 to 3 OX3;
X3 for each occurrence is independently hydrogen or (C1-C6)alkyl;
X6 for each occurrence is independently hydrogen, optionally substituted (C1-C6)alkyl, (C2-C6)halogenated alkyl, optionally substituted (C3-C7)cycloalkyl, (C3-C7)-halogenatedcycloalkyl, where optionally substituted (C1-C6)alkyl and optionally substituted (C3-C7)cycloalkyl in the definition of X6 is optionally independently substituted with hydroxyl, (C1-C4)alkoxy, carboxyl, CONH2, xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94CO2(C1-C4)alkyl, 1H-tetrazol-5-yl or 1 or 2 (C1-C4)alkyl; or
where there are two X6 groups on one atom and both X6 are (C1-C6)alkyl, the two (C1-C6)alkyl groups may be optionally joined and, together with the atom to which the two X6 groups are attached, form a 4- to 9- membered ring optionally having oxygen, sulfur or NX7;
X7 is hydrogen or (C1-C6)alkyl optionally substituted with hydroxyl; and
m for each occurrence is independently 0, 1 or 2;
with the proviso that:
X6 and X12 cannot be hydrogen when it is attached to C(O) or SO2 in the form C(O)X6, C(O)X12, SO2X6 or SO2X12;
when R2 is hydrogen then R1 is not xe2x80x94CHxe2x95x90CH-phenyl;
when R2 is H and R1 is xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94Ph, then Z100 is not BOC;
when R2 is H and R1 is then Z100 is not BOC;
when R2 is H and R1 is xe2x80x94CH2xe2x80x94C(CH3)xe2x95x90CH2, then Z100 is not BOC; and
when R2 is phenyl and R1 is xe2x80x94CH3, then Z100 is not CH3C(O)xe2x80x94.
A group of compounds preferred among the foregoing group of compounds of formula (III), designated xe2x80x9cCC Groupxe2x80x9d, are those compounds wherein w is 0 or 1; n 1;
Z100 is BOC, methyl, benzyl or CBZ;
R1 is hydrogen, xe2x80x94(CH2)qxe2x80x94(C3-C7)cycloalkyl, xe2x80x94(CH2)txe2x80x94A1 or (C1-C10)alkyl where the (C1-C10)alkyl and (C3-C7)cycloalkyl groups are optionally substituted with 1 to 3 fluoro and A1 in the definition of R1 is optionally substituted with 1 to 3 substituents independently selected from the group consisting of F, Cl, Me, OMe, CF3, OCF3 and OCF2H;
R2 is hydrogen, (C1-C8)alkyl, xe2x80x94(C0-C3)alkyl-(C3-C7)cycloalkyl, phenyl, or xe2x80x94(C1-C3)alkyl-phenyl where the alkyl and phenyl groups are optionally substituted with 1 to 3 substituents independently selected from the group consisting of F, CF3, OH and OMe.
A group of compounds preferred among the xe2x80x9cCC Groupxe2x80x9d compounds, designated xe2x80x9cDD Groupxe2x80x9d, contains those compounds of xe2x80x9cCC Groupxe2x80x9d wherein Z100 is BOC; w is 1; e is 0; R1 is xe2x80x94CH2-pyridyl, xe2x80x94CH2-thiazolyl, or xe2x80x94CH2-phenyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of fluoro and chloro; and R2 is hydrogen, (C1-C4)alkyl or phenyl where the (C1-C4)alkyl or phenyl groups in the definition of R2 is optionally substituted with 1 to 3 substituents independently selected from the group consisting of fluoro, hydroxy and methoxy.
Compounds which are preferred among the xe2x80x9cDD Groupxe2x80x9d compounds is the diastereomeric mixture of a compound wherein R1 is xe2x80x94CH2-phenyl and R2 is methyl or hydrogen; and the separated 3a-(R) and 3a-(S) isomers are preferred of the diastereomeric mixture.
Yet another group of compounds which are useful in the synthesis of the compounds of formula (I) contains those compounds of the formula 
the racemic-diastereomeric mixtures and optical isomers of said compounds wherein
Z200 is t-BOC, CBZ, CF3C(O)xe2x80x94, FMOC, TROC, trityl, tosyl or optionally substituted benzyl which is optionally substituted with methoxy, dimethoxy or nitro;
e is 0 or 1;
n and w are each independently 0, 1 or 2, provided that w and n cannot both be 0 at the same time;
Y is oxygen or sulfur;
R1 is hydrogen, xe2x80x94CN, xe2x80x94(CH2)qN(X6)C(O)X6, xe2x80x94(CH2)qN(X6)C(O)(CH2)txe2x80x94A1, xe2x80x94(CH2)qN(X6)SO2(CH2)txe2x80x94A1, xe2x80x94(CH2)qN(X6)SO2X6, xe2x80x94(CH2)qN(X6)C(O)N(X6)(CH2)txe2x80x94A1, xe2x80x94(CH2)qN(X6)C(O)N(X6)(X6), xe2x80x94(CH2)qC(O)N(X6)(X6), xe2x80x94(CH2)qC(O)N(X6)(CH2)txe2x80x94A1, xe2x80x94(CH2)qC(O)OX6), xe2x80x94(CH2)qC(O)O(CH2)txe2x80x94A1, xe2x80x94(CH2)qOX6, xe2x80x94(CH2)qOC(O)X6, xe2x80x94(CH2)qOC(O)(CH2)txe2x80x94A1, xe2x80x94(CH2)qOC(O)N(X6)(CH2)txe2x80x94A1, xe2x80x94(CH2)qOC(O)N(X6)(X6), xe2x80x94(CH2)qC(O)X6, xe2x80x94(CH2)qC(O)(CH2)txe2x80x94A1, xe2x80x94(CH2)qN(X6)C(O)OX6, xe2x80x94(CH2)qN(X6)SO2N(X6)(X6), xe2x80x94(CH2)qS(O)mX6, xe2x80x94CH2)qS(O)m(CH2)txe2x80x94A1, xe2x80x94(C1-C10)alkyl, xe2x80x94(CH2)txe2x80x94A1, xe2x80x94(CH2)qxe2x80x94(C3-C7)cycloalkyl, xe2x80x94(CH2)qxe2x80x94Y1xe2x80x94(C1-C6)alkyl, xe2x80x94(CH2)qxe2x80x94Y1xe2x80x94(CH2)txe2x80x94A1 or xe2x80x94(CH2)qxe2x80x94Y1xe2x80x94(CH2)txe2x80x94(C3-C7)cycloalkyl;
where the alkyl and cycloalkyl groups in the definition of R1 are optionally substituted with (C1-C4)alkyl, hydroxyl, (C1-C4)alkoxy, carboxyl, CONH2, xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94CO2(C1-C4)alkyl ester, 1H-tetrazol-5-yl or 1 to 3 fluoro;
Y1 is O, S(O)m, xe2x80x94C(O)NX6, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94N(X6)C(O), xe2x80x94C(O)NX6, xe2x80x94C(O)O, xe2x80x94OC(O)N(X6) or xe2x80x94OC(O);
q is 0, 1, 2, 3 or 4;
t is 0, 1, 2 or 3;
said (CH2)q group and (CH2)t group may each be optionally substituted with hydroxyl, (C1-C4)alkoxy, carboxyl, xe2x80x94CONH2, xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94CO2(C1-C4)alkyl, 1H-tetrazol-5-yl, 1 to 3 fluoro or 1 or 2 (C1-C4)alkyl;
R2 is hydrogen, (C1-C8)alkyl, xe2x80x94(C0-C3)alkyl-(C3-C8)cycloalkyl, xe2x80x94(C1-C4)alkyl-A1 or A1; where the alkyl groups and the cycloalkyl groups in the definition of R2 are optionally substituted with hydroxyl, xe2x80x94C(O)OX6, xe2x80x94C(O)N(X6)(X6), xe2x80x94N(X6)(X6), xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94C(O)A1, xe2x80x94C(O)(X6), CF3, CN or 1 to 3 halogen;
R3 is A1, (C1-C10)alkyl, xe2x80x94(C1-C6)alkyl-A1, xe2x80x94(C1-C6)alkyl-(C3-C7)cycloalkyl, xe2x80x94(C1-C5)alkyl-Xxe2x80x94(C1-C5)alkyl, xe2x80x94(C1-C5)alkyl-X1xe2x80x94(C0-C5)alkyl-A1 or xe2x80x94(C1-C5)alkyl-X1xe2x80x94(C1-C5)alkyl-(C3-C7)cycloalkyl;
where the alkyl groups in the definition of R3 is optionally substituted with xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94C(O)OX3, 1 to 5 halogens or 1 to 3 OX3;
X1 is O, S(O)m, xe2x80x94N(X2)C(O)xe2x80x94, xe2x80x94C(O)N(X2)xe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94C(O)O, xe2x80x94CX2xe2x95x90CX2xe2x80x94, xe2x80x94N(X2)C(O)Oxe2x80x94, xe2x80x94OC(O)N(X2)xe2x80x94or Cxe2x89xa1Cxe2x80x94;
R4 is hydrogen, (C1-C6)alkyl or (C3-C7)cycloalkyl, or R4 is taken together with R3 and the carbon atom to which they are attached and form (C5-C7)cycloalkyl, (C5-C7)cycloalkenyl, a partially saturated or fully saturated 4- to 8-membered ring having 1 to 4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen, or is a bicyclic ring system consisting of a partially saturated or fully saturated 5- or 6-membered ring, fused to a partially saturated, fully unsaturated or fully saturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of ndtrogen, sulfur and oxygen;
X4 is hydrogen or (C1-C6)alkyl or X4 is taken together with R4 and the nitrogen atom to which X4 is attached and the carbon atom to which R4 is attached and form a five to seven membered ring;
R6 is a bond or is 
where a and b are independently 0, 1, 2 or 3;
X5 and X5a are each independently selected from the group consisting of hydrogen, trifluoromethyl, A1 and optionally substituted (C1-C6)alkyl;
the optionally substituted (C1-C6)alkyl in the definition of X5 and X5a is optionally substituted with a substituent selected from the group consisting of A1, xe2x80x94OX2, xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94C(O)OX2, (C3-C7)cycloalkyl, xe2x80x94N(X2)(X2) and xe2x80x94C(O)N(X2)(X2);
or the carbon bearing X5 and X5a forms an alkylene bridge with the nitrogen atom bearing Z200 and R8 where the alkylene bridge contains 1 to 5 carbon atoms provided that X5 or X5a but not both may be on the carbon atom and Z200 or R8 but not both may be on the nitrogen atom;
or X5 is taken-together with X5a and the carbon atom to which they are attached and form a partially saturated or fully saturated 3- to 7-membered ring, or a partially saturated or fully saturated 4- to 8-membered ring having 1 to 4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen;
or X5 is taken together with X5a and the carbon atom to which they are attached and form a bicyclic ring system consisting of a partially saturated or fully saturated 5- or 6-membered ring, optionally having 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen, fused to a partially saturated, fully saturated or fully unsaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen;
Z1 is a bond, O or Nxe2x80x94X2, provided that when a and b are both 0 then Z1 is not Nxe2x80x94X2 or O;
R8 is hydrogen or optionally substituted (C1-C6)alkyl;
where the optionally substituted (C1-C6)alkyl in the definition of R8 is optionally independently substituted with A1, xe2x80x94C(O)Oxe2x80x94(C1-C6)alkyl, xe2x80x94S(O)m(C1-C6)alkyl, 1 to 5 halogens, 1 to 3 hydroxy, 1 to 3 xe2x80x94Oxe2x80x94C(O)(C1-C10)alkyl or 1 to 3 (C1-C6)alkoxy; or
A1 for each occurrence is independently (C5-C7)cycloalkenyl, phenyl or a partially saturated, fully saturated or fully unsaturated 4- to 8-membered ring optionally having 1 to 4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen, or a bicyclic ring system consisting of a partially saturated, fully unsaturated or fully saturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen, fused to a partially saturated, fully saturated or fully unsaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen;
A1 for each occurrence is independently optionally substituted, in one or optionally both rings if A1 is a bicyclic ring system, with up to three substituents, each substituent independently selected from the group consisting of F, Cl, Br, I, OCF3, OCF2H, CF3, CH3, OCH3,xe2x80x94OX6, xe2x80x94C(O)N(X6)(X6), xe2x80x94C(O)OX6, oxo, (C1-C6)alkyl, nitro, cyano, benzyl, xe2x80x94S(O)m(C1-C6)alkyl, 1H-tetrazol-5-yl, phenyl, phenoxy, phenylalkyloxy, halophenyl, methylenedloxy, xe2x80x94N(X6)(X6), xe2x80x94N(X6)C(O)(X6), xe2x80x94SO2N(X6)(X6), xe2x80x94N(X6)SO2-phenyl, xe2x80x94N(X6)SO2X6, xe2x80x94CONX11X12, xe2x80x94SO2NX11X12, xe2x80x94NX6SO2X12, xe2x80x94NX6CONX11X12, xe2x80x94NX6SO2NX11X12, xe2x80x94NX6C(O)X12, imidazolyl, thiazolyl and tetrazolyl, provided that if A1 is optionally substituted with methylenedioxy then it can only be substituted with one methylenedioxy;
where X11 is hydrogen or optionally substituted (C1-C6)alkyl;
the optionally substituted (C1-C6)alkyl defined for X11 is optionally independently substituted with phenyl, phenoxy, (C1-C6)alkoxycarbonyl, xe2x80x94S(O)m(C1-C6)alkyl, 1 to 5 halogens, 1 to 3 hydroxy, 1 to 3 (C1-C10)alkanoyloxy or 1 to 3 (C1-C6)alkoxy;
X12 is hydrogen, (C1-C6)alkyl, phenyl, thiazolyl, imidazolyl, furyl or thienyl, provided that when X12 is not hydrogen, X12 is optionally substituted with one to three substituents independently selected from the group consisting of Cl, F. CH3, OCH3, OCF3 and CF3;
or X11 and X12 are taken together to form xe2x80x94(CH2)rxe2x80x94L1xe2x80x94(CH2)rxe2x80x94;
L1 is C(X2)(X2), O, S(O)m or N(X2);
r for each occurrence is independently 1, 2 or 3;
X2 for each occurrence is independently hydrogen, optionally substituted (C1-C6)alkyl, or optionally substituted (C3-C7)cycloalkyl, where the optionally substituted (C1-C6)alkyl and optionally substituted (C3-C7)cycloalkyl in the definition of X2 are optionally independently substituted with xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94C(O)OX3, 1 to 5 halogens or 1 to 3 xe2x80x94OX3; 
X3 for each occurrence is independently hydrogen or (C1-C6)alkyl;
X6 for each occurrence is independently hydrogen, optionally substituted (C1-C6)alkyl, (C2-C6)halogenated alkyl, optionally substituted (C3-C7)cycloalkyl, (C3-C7)-halogenatedcycloalkyl, where optionally substituted (C1-C6)alkyl and optionally substituted (C3-C7)cycloalkyl in the definition of X6 is optionally independently substituted with hydroxyl, (C1-C4)alkoxy, carboxyl, CONH2, xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94CO2(C1-C4)alkyl, 1H-tetrazol-5-yl or 1 or 2 (C1-C4)alkyl; or when there are two X6 groups on one atom and both X6 are (C1-C6)alkyl, the two (C1-C6)alkyl groups may be optionally joined and, together with the atom to which the two X6 groups are attached, form a 4- to 9-membered ring optionally having oxygen, sulfur or NX7;
X7 is hydrogen or (C1-C6)alkyl optionally substituted by hydroxyl; and
m for each occurrence is independently 0, 1 or 2; with the proviso that:
X6 and X12 cannot be hydrogen when it is attached to C(O) or SO2 in the form C(O)X6, C(O)X12, SO2X6 or SO2X12; and
when R6 is a bond then L is N(X2) and each r in the definition xe2x80x94(CH2)rxe2x80x94Lxe2x80x94(CH2)rxe2x80x94 is 2 or 3.
Compounds which are preferred of the foregoing compounds of formula (IV) is the compound wherein e is O; Y is O; R1 is xe2x80x94CH2-phenyl; R2 is methyl or hydrogen; n is 1; w is 1; R3 is xe2x80x94CH2xe2x80x94Oxe2x80x94CH2-phenyl; R4 is hydrogen; X4 is hydrogen; R6 is xe2x80x94C(CH3)2xe2x80x94; Z200 is BOC and R8 is hydrogen.
This invention also provides:
a method for increasing levels of endogenous growth hormone in a human or other animal which comprises administering to such human or other animal an effective amount of a compound of Formula I;
a pharmaceutical composition useful for increasing the endogenous production or release of growth hormone in a human or other animal which comprises an inert carrier and an effective amount of a compound of Formula I;
a pharmaceutical composition useful for increasing the endogenous production or release of growth hormone in a human or other animal which comprises an inert carrier, an effective amount of a compound of Formula I and another growth hormone secretagogue such as, GHRP-6, Hexarelin, GHRP-1, IGF-1, IGF-2, B-HT920 or growth hormone releasing factor (GRF) or an analog thereof;
a method for the treatment or prevention of osteoporosis which comprises administering to a human or other animal in need of such treatment or prevention an amount of a compound of Formula I which is effective in treating or preventing osteoporosis;
a method for the treatment or prevention of osteoporosis which comprises administering to a human or other animal with osteoporosis a combination of a bisphosphonate compound such as alendronate, and especially preferred is the bisphosphonate compound ibandronate, and a compound of Formula I;
a method for the treatment -or prevention of osteoporosis which comprises administering to a human or other animal with osteoporosis a combination of estrogen or Premarin(copyright) and a compound of Formula I and optionally progesterone;
a method to increase IGF-1 levels in IGF-1 deficient humans or other animals which comprises administering to a human or other animal with IGF-1 deficiency a compound of Formula 1;
a method for the treatment of osteoporosis which comprises administering to a human or other animal with osteoporosis a combination of an estrogen agonist or antagonist such as tamoxifen, droloxifene, raloxifene and idoxifene and a compound of Formula 1;
a particularly preferred method for the treatment of osteoporosis comprises administering to a human or other animal with osteoporosis a combination of an estrogen agonist or antagonist such as Cis-6-(4fluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8tetrahydro-naphthalene2-ol;
(xe2x88x92)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;
cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;
cis-1-[6xe2x80x2-pyrrolodinoethoxy-3xe2x80x2-pyridyl]-2phenyl-6-hydroxy-1,2,3,4-tetrahydro-naphthalene;
1-(4xe2x80x2-pyrrolidinoethoxyphenyl)-2-(4xe2x80x3-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline;
cis-6-(4-hydroxyphenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol; or
1-(4xe2x80x2-pyrrolidinolethoxyphenyl)-2-phenyl6-hydroxy-1,2,3,4-tetrahydro-isoquinoline and a compound of Formula I;
a method for the treatment of osteoporosis which comprises administering to a human or other animal with osteoporosis a combination of calcitonin and a compound of Formula I;
a method for increasing muscle mass, which method comprises administering to a human or other animal in need of such treatment an amount of a compound of Formula I which is effective in promoting release of endogenous growth hormone; and
a method for promoting growth in growth hormone deficient children which comprises administering to a growth-hormon-edeficient child a compound of Formula I which is effective in promoting release of endogenous growth hormone.
This invention further provides a method for treating or preventing diseases or conditions which may be treated or prevented by growth hormone which comprises administering to a human or other animal in need of such treatment or prevention an amount of a compound of Formula I which is effective in promoting release of endogenous growth hormone.
In another aspect, this invention provides methods for treating or preventing congestive heart failure, frailty associated with aging, and obesity which comprise administering to a human or other animal in need of such treatment or prevention an amount of a compound of Formula I which is effective in promoting release of endogenous growth hormone; of the instant method it is preferred that the disease or condition to be treated or prevented is congestive heart failure or frailty associated with aging.
In another aspect, this invention provides methods for accelerating bone fracture repair, attenuating protein catabolic response after a major operation, reducing cachexia and protein loss due to chronic illness such as AIDS and cancer, accelerating wound healing, and accelerating the recovery of bum patients or patients having undergone major surgery, which comprise administering to a human or other animal in need of such treatment an amount of a compound of Formula I which is effective in promoting release of endogenous growth hormone; of the instant method a preferred method of use is to accelerate bone fracture repair or for accelerating the recovery of patients having undergone major surgery.
In yet another aspect, this invention provides methods for improving muscle strength, mobility, maintenance of skin thickness, metabolic homeostasis and renal homeostasis, which comprise administering to a human or other animal in need of such treatment an amount of a compound of claim 1 which is effective in promoting release of endogenous growth hormone.
The instant compounds promote the release of growth hormone which are stable under various physiological conditions and may be administered parenterally, nasally or by the oral route.
One of ordinary skill will recognize that certain substituents listed in this invention may have reduced chemical stability when combined with one another or with heteroatoms in the compounds. Such compounds with reduced chemical stability are not preferred.
In general the compounds of Formula I can be made by processes which include processes known in the chemical arts for the production of compounds. Certain processes for the manufacture of Formula I compounds are provided as further features of the invention and are illustrated by the following reaction schemes.
In the above structural formulae and throughout the instant application, the following terms have the indicated meanings unless expressly stated otherwise:
The alkyl groups are intended to include those alkyl groups of the designated length in either a straight or branched configuration which may optionally contain double or triple bonds. Exemplary of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, hexyl, isohexyl, allyl, ethynyl, propenyl, butadienyl, hexenyl and the like.
When the definition C0-alkyl occurs in the definition, it means a single covalent bond.
The alkoxy groups specified above are intended to include those alkoxy groups of the designated length in either a straight or branched configuration which may optionally contain double or triple bonds. Exemplary of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy, allyloxy, 2-propynyloxy, isobutenyloxy, hexenyloxy and the like.
The term xe2x80x9chalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d is intended to include the halogen atoms fluorine, chlorine, bromine and iodine.
The term xe2x80x9chalogenated alkylxe2x80x9d is intended to include an alkyl group as defined hereinabove substituted by one or more halogen atoms as defined hereinabove.
The term xe2x80x9chalogenated cycloalkylxe2x80x9d is intended to include a cycloalkyl group substituted by one or more halogen atoms as defined hereinabove.
The term xe2x80x9carylxe2x80x9d is intended to include phenyl and naphthyl and aromatic 5- and 6-membered rings with 1 to 4 heteroatoms or fused 5- or 6-membered bicyclic rings with 1 to 4 heteroatoms of nitrogen, sulfur or oxygen. Examples of such heterocyclic aromatic rings are pyridine, thiophene (also known as thienyl), furan, benzothiophene, tetrazole, indole, N-methylindole, dihydroindole, indazole, N-formylindole, benzimidazole, thiazole, pyrimidine, and thiadiazole.
The chemist of ordinary skill will recognize that certain combinations of heteroatom-containing substituents listed in this invention define compounds which will be less stable under physiological conditions (e.g., those containing acetal or aminal linkages). Accordingly, such compounds are less preferred.
The expression xe2x80x9cprodrugxe2x80x9d refers to compounds that are drug precursors, which following administration, release the drug in vivo via some chemical or physiological process (e.g., a prodrug on being brought to the physiological pH is converted to the desired drug form). Exemplery prodrugs upon cleavage release the corresponding free acid, and such hydrolyzable ester-forming residues of the compounds of this invention include but are not limited to carboxylic acid substituents (e.g., R1 is xe2x80x94(CH2)qC(O)2X6 where X6 is hydrogen, or R2 or A1 contains carboxylic acid) wherein the free hydrogen is replaced by (C1-C4)alkyl, (C2-C12)alkanoyloxymethyl, (C4-C9)1-(alkanoyloxy)ethyl, 1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1xe2x80x94(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(C1-C2)alkylamino(C2-C3)alkyl (such as xcex2-dimethylaminoethyl), carbamoyl-(C1-C2)alkyl, N,N-di(C1-C2)-alkylcarbamoyl-(C1-C2)alkyl and piperidino-, pyrrolidino- or morpholino(C2-C3)alkyl.
Other exemplary prodrugs release an alcohol of Formula I wherein the free hydrogen of the hydroxyl substituent (e.g., R1 contains hydroxyl) is replaced by (C1-C6)alkanoyloxymethyl, 1-((C1-C6)alkanoyloxy)ethyl, 1-methyl-1-((C1-C6)alka-noyloxy)ethyl, (C1-C6)alkoxycarbonyloxymethyl, N-(C1-C6)alkoxy-carbonylamino-methyl, succinoyl, (C1-C6)alkanoyl, xcex1-amino(C1-C4)alkanoyl, arylacetyl and xcex1-aminoacyl, or xcex1-aminoacyl-xcex1-aminoacyl wherein said xcex1-aminoacyl moieties are independently any of the naturally occurring L-amino acids found in proteins, P(O)(OH)2, xe2x80x94P(O)(O(C1-C6)alkyl)2 or glycosyl (the radical resulting from detachment of the hydroxyl of the hemiacetal of a carbohydrate).
Prodrugs of this invention where a carboxyl group in a carboxylic acid of Formula (I) is replaced by an ester may be prepared by combining the carboxylic acid with the appropriate alkyl halide in the presence of a base such as potassium carbonate in an inert solvent such as DMF at a temperature of about 0xc2x0 C. to 100xc2x0 C. for about 1 to about 24 hours. Alternatively, the acid is combined with the appropriate alcohol as solvent in the presence of a catalytic amount of acid such as concentrated sulfuric acid at a temperature of about 20xc2x0 C. to 120xc2x0 C., preferably at reflux, for about 1 hour to about 24 hours. Another method is the reaction of the acid in an inert solvent such as THF, with concomitant removal of the water being produced by physical (e.g., Dean Stark trap) or chemical (e.g., molecular sieves) means.
Prodrugs of this invention where an alcohol function has been derivatized as an ether may be prepared by combining the alcohol with the appropriate alkyl bromide or iodide in the presence of a base such as potassium carbonate in an inert solvent such as DMF at a temperature of about 0xc2x0 C. to 100xc2x0 C. for about 1 to about 24 hours. Alkanoylaminomethyl ethers may be obtained by reaction of the alcohol with a bis-(alkanoylamino)methane in the presence of a catalytic amount of acid in an inert solvent such as THF, according to a method described in U.S. Pat. No. 4,997,984. Alternatively, these compounds may be prepared by the methods described by Hoffman et al. in J. Org. Chem. 1994, 59, p. 3530.
Certain of the above defined terms may occur more than once in the above formula and upon such occurrence each term shall be defined independently of the other.
Throughout the specification and appendent claims the following abbreviations are used with the following meanings:
The compounds of the instant invention all have at least one asymmetric center as noted by the asterisk in the structural Formula I, above. Additional asymmetric centers may be present on the molecule depending upon the nature of the various substituents on the molecule. Each such asymmetric center will produce two optical isomers and it is intended that all such optical isomers, as separated, pure or partially purified optical isomers, racemic mixtures or diastereomeric mixtures thereof, be included within the scope of the instant invention. In the case of the asymmetric center represented by the asterisk, it has been found that the absolute stereochemistry of the more active and thus more preferred isomer is shown in Formula IA. This preferred absolute configuration also applies to Formula I. 
With the R4 substituent as hydrogen, the spatial configuration of the asymmetric center corresponds to that in a D-amino acid. In most cases this is also designated an R-configuration although this will vary according to the values of R3 and R4 used in making R- or S-stereochemical assignments.
The instant compounds are generally isolated in the form of their pharmaceutically acceptable acid addition salts, such as the salts derived from using inorganic and organic acids. Examples of such acids are hydrochloric, nitric, sulfuric, phosphoric, formnic, acetic, trifluoroacetic, propionic, maleic, succinic, D-tartaric, L-tartaric, malonic, methane sulfonic and the like. In addition, certain compounds containing an acidic function such as a carboxy can be isolated in the form of their inorganic salt in which the counter-ion can be selected from sodium, potassium, lithium, calcium, magnesium and the like, as well as from organic bases.
The pharmaceutically acceptable salts are formed by taking about 1 equivalent of a compound of formula (I) and contacting it with about 1 equivalent of the appropriate corresponding acid of the salt which is desired. Work-up and isolation of the resulting salt is well-known to those of ordinary skill in the art.
The growth hormone releasing compounds of Formula I are useful in vitro as unique tools for understanding how growth hormone secretion is regulated at the pituitary level. This includes use in the evaluation of many factors thought or known to influence growth hormone secretion such as age, sex, nutritional factors, glucose, amino acids, fatty acids, as well as fasting and non-fasting states. In addition, the compounds of this invention can be used in the evaluation of how other hormones modify growth hormone releasing activity. For example, it has already been established that somatostatin inhibits growth hormone release.
The compounds of Formula I can be administered to animals, including humans, to release growth hormone in vivo. The compounds are useful for treatment of symptoms related to GH deficiency, stimulate growth or enhance feed efficiency of animals raised for meat production to improve carcass quality; to increase milk production in dairy cattle; improvement of bone or wound healing and improvement in vital organ function. The compounds of the present invention by inducing endogenous GH secretion will after body composition and modify other GH-dependent metabolic, immunologic or developmental processes. For example, the compounds of the present invention can be given to chickens, turkeys, livestock animals (such as sheep, pigs, horses, cattle, etc.)i companion animals (e.g., dogs) or may have utility in aquaculture to accelerate growth and improve the protein/fat ratio. In addition, these compounds can be administered to humans in vivo as a diagnostic tool to directly determine whether the pituitary is capable of releasing growth hormone. For example, the compounds of Formula I can be administered in vivo to children. Serum samples taken before and after such administration can be assayed for growth hormone. Comparison of the amounts of growth hormone in each of these samples would be a means for directly determining the ability of the patient""s pituitary to release growth hormone.
Accordingly, the present invention includes within its scope pharmaceutical compositions comprising, as an active ingredient, at least one of the compounds of Formula I in association with a pharmaceutically acceptable carrier. Optionally, the pharmaceutical compositions can further comprise an anabolic agent in addition to at least one of the compounds of Formula I or another compound which exhibits a different activity, e.g., an antibiotic growth permittant or an agent to treat osteoporosis or with other pharmaceutically active materials wherein the combination enhances efficacy and minimizes side effects.
Growth promoting and anabolic agents include, but are not limited to, TRH, PTH, diethylstilbesterol, estrogens, xcex2-agonists, theophylline, anabolic steroids, enkephalins, E series prostaglandins, compounds disclosed in U.S. Pat. No. 3,239,345, the disclosure of which is hereby incorporated by reference, e.g., zeranol;
compounds disclosed in U.S. Patent No. 4,036,979, the disclosure of which is hereby incorporated by reference, e.g., sulbenox; and peptides disclosed in U.S. Pat. No. 4,411,890, the disclosure of which is hereby incorporated by reference.
The growth hormone secretagogues of this invention in combination with other growth hormone secretagogues such as the growth hormone releasing peptides GHRP-6 and GHRP-1 as described in U.S. Pat. No. 4,411,890,the disclosure of which is hereby incorporated by reference, and publications WO 89/07110, WO 89/07111 and BHT920 as well as hexarelin and the newly discovered GHRP-2 as described in WO 93/04081 or growth hormone releasing hormone (GHRH, also designated GRF) and its analogs or growth hormone and its analogs or somatomedins including IGF-1 and IGF-2 or xcexc-adrenergic agonists such as clonidine or serotonin 5HTID agonists such as sumitriptan or agents which inhibit somatostatin or its release such as physostigmine and pyridostigmine, are useful for increasing the endogenous levels of GH in mammals. The combination of a GH secretagogue of this invention with GRF results in synergistic increases of endogenous growth hormone.
As is well known to those skilled in the art, the known and potential uses of growth hormone are varied and multitudinous [See xe2x80x9cHuman Growth Hormonexe2x80x9d, Strobel and Thomas, Pharmacological Reviews, 46, pg. 1-34 (1994); T. Rosen et al., Horm Res, 1995; 43: pp. 93-99; M. Degerblad et al., European Journal of Endocrinology, 1995, 133: pp.180-188; J. O. Jorgensen, European Journal of Endocrinology, 1994, 130: pp. 224-228; K. C. Copeland et al., Journal of Clinical Endocrinology and Metabolism, Vol. 78 No. 5, pp. 1040-1047; J. A. Aloi et al., Journal of Clinical Endocrinology and Metabolism, Vol. 79 No. 4, pp. 943-949; F. Cordido et al., Metab. Clin. Exp., (1995), 44(6), pp. 745-748; K. M. Fairhall et al., J. Endocrinol., (1995), 145(3), pp. 417-426; RM. Frieboes et al.,
Neuroendocrinology, (1995), 61(5), pp. 584-589; and M. Liovera et al., int. J. Cancer, (1995), 61(1), pp. 138-141]. Thus, the administration of the compounds of this invention for purposes of stimulating the release of endogenous growth hormone can have the same effects or uses as growth hormone itself. These varied uses of growth hormone may be summarized as follows: stimulating growth hormone release in elderly humans; treating growth hormone deficient adults; preventing catabolic side effects of glucocorticoids, treating osteoporosis, stimulating the immune system, acceleration of wound healing, accelerating bone fracture repair, treating growth retardation, treating congestive heart failure as disclosed in PCT publications WO 95/128173 and WO 95/128174 (an example of a method for assaying growth hormone secretagogues for efficacy in treating congestive heart failure is disclosed in R. Yang et al., Circulation, Vol. 92, No. 2, p.262, 1995), treating acute or chronic renal failure or insufficiency, treatment of physiological short stature, including growth hormone deficient children, treating short stature associated with chronic illness, treating obesity, treating growth retardation associated with Prader-Willi syndrome and Tuner""s syndrome; accelerating the recovery and reducing hospitalization of bum patients or following major surgery such as gastrointestinal surgery; treating intrauterine growth retardation, skeletal dysplasia, hypercortisonism and Cushings syndrome; replacing growth hormone in stressed patients; treating osteochondrodysplasias, Noonans syndrome, sleep disorders, Alzheimer""s disease, delayed wound healing, and psychosocial deprivation; treating of pulmonary dysfunction and ventilator dependency; attenuating protein catabolic response after a major operation; treating malabsorption syndromes, reducing cachexia and protein loss due to chronic illness such as cancer or AIDS; accelerating weight gain and protein accretion in patients on TPN (total parenteral nutrition); treating hyperinsulinemia including nesidioblastosis; adjuvant treatment for ovulation induction and to prevent and treat gastric and duodenal ulcers; stimulating thymic development and preventing age-related decline of thymic function; adjunctive therapy for patients on chronic hemodialysis; treating immunosuppressed patients and enhancing antibody response following vaccination; improving muscle strength, increasing muscle mass, mobility, maintenance of skin thickness, metabolic homeostasis, renal hemeostasis in the frail elderly; stimulating osteoblasts, bone remodelling, and cartilage growth; treating neurological diseases such as peripheral and drug induced neuropathy, Guillian-Barre Syndrome, amyotrophic lateral sclerosis, multiple sclerosis, cerebrovascular accidents and demyelinating diseases; stimulating the immune system in companion animals and treating disorders of aging in companion animals; growth promotant in livestock; and stimulating wool growth in sheep.
It will be known to those skilled in the art that there are numerous compounds now being used in an effort to treat the diseases or therapeutic indications enumerated above. Combinations of these therapeutic agents, some of which have also been mentioned above, with the growth promotant, exhibit anabolic and desirable properties of these various therapeutic agents. In these combinations, the therapeutic agents and the growth hormone secretagogues of this invention may be independently and sequentially administered or co-administered in dose ranges from one one-hundredth to one times the dose levels which are effective when these compounds and secretagogues are used singly. Combined therapy to inhibit bone resorption, prevent osteoporosis, reduce skeletal fracture, enhance the healing of bone fractures, stimulate bone formation and increase bone mineral density can be effectuated by combinations of bisphosphonates and the growth hormone secretagogues of this invention, see PCT publication WO 95/11029 for a discussion of combination therapy using bisphosphonates and GH secretagogues. The use of bisphosphonates for these utilities has been reviewed, for example, by Hamdy, N.A.T., Role of Bisphosphonates in Metabolic Bone Diseases, Trends in Endocrinol. Metab., 1993, 4, pages 19-25. Bisphosphonates with these utilities include but are not limited to alendronate, tiludronate, dimethyl-APD, risedronate, etidronate, YM-175, clodronate, pamidronate, and BM-210995 (ibandronate). According to their potency, oral daily dosage levels of the bisphosphonate of between 0.1 mg and 5 g and daily dosage levels of the growth hormone secretagogues of this invention of between 0.01 mg/kg to 20 mg/kg of body weight are administered to patients to obtain effective treatment of osteoporosis.
The compounds of this invention may be combined with a mammalian estrogen agonist/antagonist. Any estrogen agonist/antagonist may be used as the second compound of this invention. The term estrogen agonist/antagonist refers to compounds which bind with the estrogen receptor, inhibit bone turnover and prevent bone loss. In particular, estrogen agonists are herein defined as chemical compounds capable of binding to the estrogen receptor sites in mammalian tissue, and mimicking the actions of estrogen in one or more tissue. Estrogen antagonists are herein defined as chemical compounds capable of binding to the estrogen receptor sites in mammalian tissue, and blocking the actions of estrogen in one or more tissues. Such activities are readily determined by those skilled in the art according to standard assays including estrogen receptor binding assays, standard bone histomorphometric and densitometer methods (see Eriksen E. F. et al., Bone Histomorphometry, Raven Press, New York, 1994, pages 1-74; Grier S. J. et al., The Use of Dual-Energy X-Ray Absorptiometry In Animals, Inv. Radiol., 1996, 31(1):50-62; Wahner H. W. and Fogelman I., The Evaluation of Osteoporosis: Dual Energy X-Ray Absorptiometry in Clinical Practice., Martin Dunit Ltd., London 1994, pages 1-296). A variety of these compounds are described and referenced below, however, other estrogen agonists/antagonists will be known to those skilled in the art. A preferred estrogen agonist/antagonist is droloxifene: (phenol, 3-[1-[4-[2-(dimethylamino)ethoxy]-phenyl]-2-phenyl-1-butenyl]xe2x80x94, (E)-) and associated compounds which are disclosed in U.S. Pat. No. 5,047,431 (the disclosure of which is hereby incorporated by reference).
Another preferred estrogen agonist/antagonist is tamoxifen: (ethanamine,2-[-4-(1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethyl, (Z)-2-, 2-hydroxy-1,2,3-propanetri-carboxylate (1:1)) and associated compounds which are disclosed in U.S. Pat. No. 4,536,516 (the disclosure of which is hereby incorporated by reference). Another related compound is 4-hydroxy tamoxifen which is disclosed in U.S. Pat. No. 4,623,660 (the disclosure of which is hereby incorporated by reference).
Another preferred estrogen agonist/antagonist is raloxifene: (methanone, [-6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl][-4-[2-(1-peridinyl)ethoxy]pheny]-hydrochloride) and associated compounds which are disclosed in U.S. Pat. No. 4,418,068 (the disclosure of which is hereby incorporated by reference).
Another preferred estrogen agonist/antagonist is idoxifene: Pyrrolidine, 1-[-[-[4-[[1-(4-iodophenyl)-2-phenyl-1-Butenyl]phenoxy]ethyl] and associated compounds which are disclosed in U.S. Pat. No. 4,839,155 (the disclosure of which is hereby incorporated by reference).
Other preferred estrogen agonist/antagonists include compounds as described in commonly assigned U.S. Pat. No. 5,552,412 the disclosure of which is hereby incorporated by reference. Especially preferred compounds which are described therein are:
cis-6-(4-fluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;
(xe2x88x92)-cis-6phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;
cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;
cis-1-[6xe2x80x2-pyrrolodinoethoxy-3xe2x80x2-pyridyl]-2-phenyl-6-hydroxy-1,2,3,4-tetrahydronaphthalene;
1-(4xe2x80x2-pyrrolidinoethoxyphenyl)-2-(4xe2x80x3-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline;
cis -6-(4-hydroxyphenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyI]-5,6,7,8-tetrahydro-naphthalene-2-ol; and
1-(4xe2x80x2-pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline.
Other estrogen agonist/antagonists are described in U.S. Pat. No. 4,133,814 (the disclosure of which is hereby incorporated by reference). U.S. Pat. No. 4,133,814 discloses derivatives of 2-phenyl-3-aroyl-benzothiophene and 2-phenyl3-aroylbenzothiophene-1-oxide.
The following paragraphs provide preferred dosage ranges for various anti-resorptive agents.
The amount of the anti-resorptive agent to be used is determined by its activity as a bone loss inhibiting agent. This activity is determined by means of an individual compound""s pharmacoidnetics and its minimal maximal effective dose in inhibition of bone loss using a protocol such as those referenced above.
In general an effective dosage for the activities of this invention, for example the treatment of osteoporosis, for the estrogen agonists/antagonists (when used in combination with a compound of Formula I of this invention) is in the range of 0.01 to 200 mg/kg/day, preferably 0.5 to 100 mg/kg/day.
In particular, an effective dosage for droloxifene is in the range of 0.1 to 40 mg/kg/day, preferably 0.1 to 5 mg/kg/day.
In particular, an effective dosage for raloxifene is in the range of 0.1 to 100 mg/kg/day, preferably 0.1 to 10 mg/kg/day.
In particular, an effective dosage for tamoxifen is in the range of 0.1 to 100 mg/kg/day, preferably 0.1 to 5 mg/kg/day.
In particular, an effective dosage for
cis-6-(4-fluoro-phenyl)-5-[4-(2-piperidin-1 -yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene2-ol;
(xe2x88x92)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol;
cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol,
cis-1-[6xe2x80x2-pyrrolodinoethoxy-3xe2x80x2-pyridyl]-2-phenyl-6-hydroxy-1,2,3,4-tetrahydronaphthalene;
1-(4xe2x80x2-pyrrolidinoethoxyphenyl)-2-(4xe2x80x3-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline;
cis-6-(4-hydroxyphenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalene-2-ol; or
1-(4-pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline is in the range of 0.0001 to 100 mg/kg/day, preferably 0.001 to 10 mg/kg/day.
In particular, an effective dosage for 4-hydroxy tamoxifen is in the range of 0.0001 to 100 mg/kg/day, preferably 0.001 to 10 mg/kg/day.
Compounds that have the ability to stimulate GH secretion from cultured rat pituitary cells are identified using the following protocol. This test is also useful for comparison to standards to determine dosage levels. Cells are isolated from pituitaries of 6-week old male Wistar rats. Following decapitation, the anterior pituitary lobes are removed into cold, sterile Hank""s balanced salt solution without calcium or magnesium (HBSS). Tissues are finely minced, then subjected to two cycles of mechanically assisted enzymatic dispersion using 10 U/mL bacterial protease (EC 3.4.24.4, Sigma P-6141) in HBSS. The tissue-enzyme mixture is stirred in a spinner flask at 30 rpm in a 5% C2 atmosphere at about 37xc2x0 C. for about 30 min, with manual trituration after about 15 min and about 30 min using a 10-mL pipet. This mixture is centrifuged at 200xc3x97g for about 5 min. Horse serum is added to the supernatant to neutralize excess protease. The pellet is resuspended in fresh protease, stirred for about 30 min more under the previous conditions, and manually triturated, ultimately through a 23-gauge needle. Again, horse serum is added, then the cells from both digests are combined, pelleted (200 xc3x97g for about 15 min), washed, resuspended in culture medium and counted. Cells are plated at 6.0-6.5xc3x97104 cells per cm2 in 48well Costar dishes and cultured for 3-4 days in Dulbecco""s Modified Eagle Medium (D-MEM) supplemented with 4.5 g/L glucose, 10% horse serum, 2.5% fetal bovine serum, 1% non-essential amino acids, 100 U/mL nystatin and 50 mg/mL gentamycin sulfate before assaying for GH secretion.
Just prior to assay, culture wells are rinsed twice, then equilibrated for about 30 minutes in release medium (D-MEM buffered with 25 mM Hepes, pH 7.4 and containing 0.5% bovine serum albumin at 37xc2x0 C.). Test compounds are dissolved in DMSO, then diluted into pre-warmed release medium. Assays are run in quadruplicate. The assay is initiated by adding 0.5 mL of release medium (with vehicle or test compound) to each culture well. Incubation is carried out at about 37xc2x0 C. for about 15 minutes, then terminated by removal of the culture medium, which is centrifuged at 2000 xc3x97g for about 15 minutes to remove cellular material. Rat growth hormone concentrations in the supernatants are determined by a standard radioimmunoassay protocol using a rat growth hormone reference preparation (NIDDK-rGH-RP-2) and rat growth hormone antiserum raised in monkey (NIDDK-anti-rGH-S-5) obtained from Dr. A. Parlow (Harbor-UCLA Medical Center, Torrence, Calif.). Additional rat growth hormone (1.5U/mg, #G2414, Scripps Labs, San Diego, Calif.) is iodinated to a specific activity of approximately 30 xcexcCi/xcexcg by the chloramine T method for use as tracer. Immune complexes are obtained by adding goat antiserum to monkey IgG (Organon Teknika, Durham, N.C.) plus polyethylene glycol, MW 10,000-20,000 to a final concentration of 4.3%; recovery is accomplished by centrifugation. This assay has a working range of 0.08-2.5 xcexcg rat growth hormone per tube above basal levels. Active compounds typically stimulate growth hormone release by greater than 1.4 fold. Reference: Cheng, K., Chan, W.-S., Barreto, Jr., A., Convey, E.M., Smith, R.G. 1989.
Twenty-one day old female Sprague-Dawley rats (Charles River Laboratory, Wilmington, Mass.) are allowed to acclimate to local vivarium conditions (24xc2x0 C., 12 hr light, 12 hr dark cycle) for approximately 1 week before compound testing. All rats are allowed access to water and a pelleted commercial diet (Agway Country Food, Syracuse N.Y.) ad libitum. The experiments are conducted in accordance with the NIH Guide for the Care and Use of Laboratory Animals.
On the day of the experiment, test compounds are dissolved in vehicle containing 1% ethanol, 1 mM acetic acid and 0.1% bovine serum albumin in saline. Each compound is tested with n=3. Rats are weighed-and anesthetized via intraperitoneal injection of sodium pentobarbital (Nembutol, 50 mg/kg body weight). Fourteen minutes after anesthetic administration, a blood sample is taken by nicking the tip of the tail and allowing the blood to drip into a microcentrifuge tube (baseline blood sample, approximately 100 xcexcl). Fifteen minutes after anesthetic administration, test compound is delivered by intravenous injection into the tail vein, with a total injection volume of 1 ml/kg body weight. Additional blood samples are taken from the tail at 5, 10 and 15 minutes after compound administration. Blood samples are kept on ice until serum separation by centrifugation (1430xc3x97g for 10 minutes at 10xc2x0 C.). Serum is stored at xe2x88x9280xc2x0 C. until serum growth hormone determination by radio-immunoassay as described above and below.
On the day of experimentation, the test compound is weighed out for the appropriate dose and dissolved in water. Doses are delivered at a volume of 0.5 ml/kg by gavage to 4 dogs for each dosing regimen. Blood samples (2 ml) are collected from the jugular vein by direct vena puncture pre-dose and at 0.08, 0.17, 0.25, 0.5, 0.75, 1, 2, 4, 6, and 8 hours post dose using 2 ml vacutainers containing lithium heparin. The prepared plasma is stored at xe2x88x9220xc2x0 C. until analysis.
Canine growth hormone concentrations are determined by a standard radioimmunoassay protocol using canine growth hormone (antigen for iodination and reference preparation AFP-1983B) and canine growth hormone antiserum raised in monkey (AFP-21452578) obtained from Dr. A. Parlow (Harbor-UCLA Medical Center, Torrence, Calif.). Tracer is produced by chloramine T-iodination of canine growth hormone to a specific activity of 20-40 xcexcCi/xcexcg. Immune complexes are obtained by adding goat antiserum to monkey IgG (Organon Teknika, Durham, N.C.) plus polyethylene glycol, MW 10,000-20,000 to a final concentration of 4.3%; recovery is accomplished by centrifugation. This assay has a working range of 0.08-2.5 xcexcg canine GH/tube.
The compounds of this invention can be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous or subcutaneous injection, or implant), nasal, vaginal, rectal, sublingual, or topical routes of administration and can be formulated with pharmaceutically acceptable carriers to provide dosage forms appropriate for each route of adrministration.
Solid dosage forms for oral administration-include capsules, tablets, pills,- powders and granules. In such solid dosage forms, the active compound is admixed with at least one inert pharmaceutically acceptable carrier such as sucrose, lactose, or starch. Such dosage forms can also comprise, as is normal practice, additional substances other than such inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, the elixirs containing inert diluents commonly used in the art, such as water. Besides such inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring and perfuming agents.
Preparations according to this invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Examples of non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate. Such dosage forms may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. They may be sterilized by, for example, filtration through a bacteria-retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
Compositions for rectal or vaginal administration are preferably suppositories which may contain, in addition to the active substance, excipients such as coca butter or a suppository wax.
Compositions for nasal or sublingual administration are also prepared with standard excipients well known in the art.
The dosage of active ingredient in the compositions of this invention may be varied; however, it is necessary that the amount of the active ingredient be such that a suitable dosage form is obtained. The selected dosage depends upon the desired therapeutic effect, on the route of administration, and on the duration of the treatment. Generally, dosage levels of between 0.0001 to 100 mg/kg of body weight daily are administered to humans and other animals, e.g., mammals, to obtain effective release of growth hormone.
A preferred dosage range is 0.01 to 5.0 mg/kg of body weight daily which can be administered as a single dose or divided into multiple doses.
The preparation of the compounds of Formula I of the present invention can be carried out in sequential or convergent synthetic routes. Syntheses detailing the preparation of the compounds of Formula I in a sequential manner are presented in the reaction schemes shown hereinbelow.
Many protected amino acid derivatives are commercially available, where the protecting groups Prt, Z100 and Z200 are, for example, BOC, CBZ, benzyl, ethoxycarbonyl groups, CF3C(O)xe2x80x94, FMOC, TROC, trityl or tosyl. Other protected amino acid derivatives can be prepared by literature methods. Some 3-oxo-2-carboxyl pyrrolidines, and 4-oxo-3-carboxyl piperidines are commercially available, and many other related pyrrolidines and 4-substituted piperidines are known in the literature.
Many of the schemes illustrated below describe compounds which contain protecting groups Prt, Z100 or Z200. Benzyloxycarbonyl groups can be removed by a number of methods including, catalytic hydrogenation with hydrogen in the presence of a palladium or platinum catalyst in a protic solvent such as methanol. Preferred catalysts are palladium hydroxide on carbon or palladium on carbon. Hydrogen pressures from 1-1000 psi may be employed; pressures from 10 to 70 psi are preferred. Alternatively, the benzyloxycarbonyl group can be removed by transfer hydrogenation.
Removal of BOC protecting groups can be carried out using a strong acid such as trifluoroacetic acid or hydrochloric acid with or without the presence of a cosolvent such as dichloromethane, ethyl acetate, ether or methanol at a temperature of about xe2x88x9230 to 70xc2x0 C., preferably about xe2x88x925 to about 35xc2x0 C.
Benzyl esters of amines can be removed by a number of methods including, catalytic hydrogenation with hydrogen in the presence of a palladium catalyst in a protic solvent such as methanol. Hydrogen pressures from 1-1000 psi may be employed; pressures from 10 to 70 psi are preferred. The addition and removal of these and other protecting groups are discussed by T. Greene in Protective Groups in Organic Synthesis, John Wiley and Sons, New York, 1981. 
The protected amino acid derivatives 1 are in many cases commercially available, where the protecting group Prt is, for example, BOC, FMOC or CBZ groups. Other amino acids can be prepared by literature methods.
As illustrated in Scheme 1, coupling of amines of formula 2 with protected amino acids of formula 1, where Prt is a suitable protecting group, is conveniently carried out in an inert solvent such as dichloromethane or DMF by a coupling reagent such as EDC or DCC in the presence of HOBT or HOAT. In the case where the amine is present as the hydrochloride salt, it is preferable to add one or two equivalents of a suitable base such as triethylamine to the reaction mixture. Alternatively, the coupling can be effected with a coupling reagent such as BOP in an inert solvent such as methanol. Such coupling reactions are generally conducted at temperatures of about xe2x88x9230xc2x0 to about 80xc2x0 C., preferably xe2x88x9210xc2x0 to about 25xc2x0 C. For a discussion of other conditions used for coupling peptides see Houben-Weyl, Vol. XV, part II, E. Wunsch, Ed., George Theime Verlag, 1974, Stuttgart. Separation of unwanted side products and purification of intermediates is achieved by chromatography on silica gel, employing flash chromatography (W. C. Still, M. Kahn and A. Mitra, J. Org. Chem. 43 2923 1978), by crystallization or by trituration.
Transformation of the compound of formula 3 into intermediates of formula 4 can be carried out by removal of the protecting group Prt as described above. Coupling of intermediates of formula 4 to amino acids of formula 5 can be effected as described above to give intermediates of formula 6. Deprotection of the amine 6 affords compounds of formula 7. 
Alternatively, compounds of formula 7 can be prepared by a convergent route as shown in Scheme 2. Intermediate esters of formula 8 can be prepared by treating amino acids 1, where Prt is a suitable protecting group, with a base such as potassium carbonate followed by an alkyl halide such as iodomethane in a suitable solvent such as DMF. Deprotection of the amine transforms 8 into 9. Alternatively, many amino acids of formula 9 are commercially available. Intermediate 10 is generated by coupling 9 to amino acid 5. The ester of intermediate 10 can be converted to intermediate acid 11 by a number of methods known in the art; for example, methyl and ethyl esters can be hydrolyzed with lithium hydroxide in a protic solvent such as aqueous methanol or aqueous THF at a temperature of about xe2x88x92200 to 120xc2x0 C., preferably about 0xc2x0 to 50xc2x0 C. In addition, removal of a benzyl group can be accomplished by a number of reductive methods including hydrogenation in the presence of platinum or palladium catalyst in a protic solvent such as methanol. Acid 11 can then be coupled to amine 2 to give intermediates of formula 6. Transformation of 6 to 7 can be achieved by removal of the protecting group Z200. 
The esters of formula 6 can be converted to intermediate acids of formula 13 by a number of methods known in the art; - for example, methyl and ethyl esters can be hydrolyzed with lithium hydroxide in a protic solvent such as aqueous methanol or aqueous THF at a temperature of about xe2x88x92200 to 120xc2x0 C., preferably about 0xc2x0 to 50xc2x0 C. In addition, removal of a benzyl group can be accomplished by a number of reductive methods including hydrogenation in the presence of platinum or palladium catalyst in a protic solvent such as methanol. Coupling the acid 13 to amine 16 generates the intermediates of formula 14. Transformation of 14 to 15 can be achieved by removal of the protecting group Z200. 
Esters of formula 17 can be prepared by treating an acid of formula 5 with hydroxysuccinimide in the presence of a coupling agent such as EDC in an inert solvent such as methylene chloride as illustrated in Scheme 4. Treatment of an ester 17 with an amino acid of formula 1 in a solvent such as dioxane, THF or DMF in the presence of a base such as diisopropylethylamine produces 11. 
As illustrated in Scheme 5, alkylation of the diphenyloxazinone of formula 18 with cinnamyl bromide in the presence of sodium bis(trimethylsilyl)amide generates 19 which is then converted to the desired (D)-2-amino-5-phenylpentanoic acid 20 by removing the protecting group (Prt) and hydrogenation over a PdCl2 catalyst. 
Treatment of an ester of formula 21 with a base such as sodium hydride in a solvent such as DMF followed by an alkyl halide 22 generates a compound of formula 23 as illustrated in Scheme 6. Treating a compound of formula 23 with a hydrazine of formula 24 such as hydrazine or methyl-hydrazine in a solvent such as refluxing ethanol, followed by concentration and heating the residue in toluene at temperatures at or near reflux results in a compound of formula 25. Alternatively, 23 can be treated with a salt of a hydrazine in the presence of sodium acetate in refluxing ethanol to give 25. Deprotection of the amine generates a compound of formula 28. Thioamides of formula 26 can be formed by treating 25 with Lawesson""s reagent in refluxing toluene or benzene. Removal of the protecting group transforms 26 into 27. 
Treatment of a compound of formula 21 with a hydrazine of formula 24 in a solvent such as refluxing ethanol, followed by concentration and heating the residue in toluene at temperatures at or near reflux results in compounds of formula 29. Alternatively, 21 can be treated with a salt of a hydrazine in the presence of sodium acetate in refluxing ethanol to give 29. The amide of formula 29 can be treated with a base such as sodium hydride in a solvent such as DMF followed by an alkyl halide to give 25. Deprotection of the amine generates a compound of formula 28. 
Reaction of a ketoester of formula 30 with a chiral amine such as alpha-methylbenzylamine with a suitable aldehyde such as formaldehyde, or reaction of a vinyl ketoester of formula 31 with a chiral amine such as alpha-methylbenzylamine with a suitable aldehyde such as formaldehyde, affords a compound of formula 32 via a double Mannich reaction. Reaction of 32 with a hydrazine generates a chiral compound of formula 33. Deprotection of the nitrogen with hydrogen and a suitable catalyst such as palladium affords compounds of formula 34. 
Treatment of a compound of formula 81 with a reducing agent such as sodium borohydride and protection of the nitrogen affords a compound of formula 82. Protection of the alcohol affords 83. Saponification of the ester affords a compound of formula 84. Reaction of 84 with thionyl chloride followed by treatment with diazomethane affords the homologated acid of formula 85. Esterification of 85 affords a compound of formula 86, which is O-deprotected to give 87. Oxidation of 87 affords a ketone of formula 88. Reaction of 88 with a hydrazine, followed by nitrogen deprotection affords a compound of formula 44. 
Treatment of a compound of formula 35 with a base such as sodium hydride in a solvent such as DMF followed by treatment with diethylcarbonate generates the ethyl ester of compound 36. Deprotection of the amine transforms 36 into 37. 
Treatment of a malonic ester of formula 38 with a base such as sodium hydride in a solvent such as DMF and subsequent hydrogenolysis of the benzyl group with hydrogen and a catalyst such as palladium in a suitable solvent such as methanol produces the ester of formula 39. Deprotection of the amine generates compounds of formula 40. 
Treatment of a ketone of formula 41 with a secondary amine such as piperidine in a suitable solvent such as benzene with removal of water affords an enamine of formula 42. Alkylation of the enamine with an alpha-haloester such as ethylbromoacetate in a suitable solvent such as benzene or THF using a suitable base such as LDA or NaN(SiMe3)2 affords a ketoester of formula 43. Reaction with a hydrazine of formula 24 affords the compound of formula 44. Deprotection of the nitrogen affords compounds of formula 45. 
Treatment of a ketoester of formula 37 with an iodonium salt such as diphenyliodonium trifluoroacetate in a suitable solvent such as t-butanol generates a ketoester of formula 46. Reaction of 46 with a hydrazine generates a compound of formula 47. Deprotection of the nitrogen affords compounds of formula 48, see Synthesis, (9), 1984 p. 709 for a detailed description. 
Treatment of a ketoester of formula 37 with an olefin such as acrylonitrile generates a ketoester of formula 49. Reaction of 49 with a hydrazine generates a compound of formula 50. Deprotection of the nitrogen affords compounds of formula 51. 
Treatment of a ketoester of formula 37 with allyl bromide and a suitable base such as sodium hydride in a suitable solvent such as DMF affords a ketoester of formula 52. Reaction of 52 with a hydrazine generates a compound of formula 53. Ozonolysis of 53 in a suitable solvent such as methylene chloride followed by treatment with a reducing agent such as dimethylsulfide affords an aldehyde of formula 54. Oxidation of 54 affords a carboxylic acid of formula 55. Curtius rearrangement of 55, followed by hydrolysis of the intermediate isocyanate affords a primary amine of formula 56. Treatment of a compound of formula 56 with an isocyanate or carbamate affords a urea of formula 57. Deprotection of the nitrogen affords compounds of formula 58. 
Treatment of a compound of formula 54 with a primary amine affords an imine of formula 59. Reduction of a compound of formula 59 affords a compound of formula 60. Treatment of a compound of formula 60 with an acylating agent affords a compound of formula 61. Deprotection of the nitrogen affords compounds of formula 62. 
Treatment of a compound of formula 54 with a reducing agent such as sodium borohydride affords a compound of formula 63. Reaction of 63 with an acylating agent such as an isocyanate or carbamate affords compounds of formula 64. Deprotection of the nitrogen affords compounds of formula 65. 
Treatment of a compound of formula 63 with a phosphine such as triphenyl phosphine and an azo compound such as diethylazodicarboxylate and an oxindole affords a compound of formula 66. Deprotection of the nitrogen affords the compound of formula 67. 
Treatment of a ketoester of formula 37 with a chiral diol and acid catalyst with removal of water in a suitable solvent such as benzene affords a chiral ketal of formula 68. Alkylation of 68 with an alkyl halide in the presence of a base such as LDA followed by acid-catalyzed hydrolysis of the ketal affords chiral ketoesters of formula 69. Reaction of 69 with a hydrazine generates chiral compounds of formula 70. Deprotection of the nitrogen affords compounds of formula 71. 
Treatment of a ketoester of formula 37 with a chiral amino acid ester such as valine t-butyl ester affords a chiral enamine of formula 72. Alkylation of 72 with an alkyl halide in the presence of a base such as LDA followed by acid-catalyzed hydrolysis of the enamine affords chiral ketoesters of formula 69. Reaction of 69 with a hydrazine generates chiral compounds of formula 70. Deprotection of the nitrogen affords compounds of formula 71. 
Deprotection of the nitrogen of 25 affords compounds of formula 28. Salt formation of 28 with a chiral acid affords a mixture of diastereomeric salts of formula 73. Crystallization of the diastereomeric salts affords the acid salt of chiral compounds of formula 70. Decomposition of the salt 70 with base liberates chiral compounds of formula 71. 
Alkylation of compounds of formula 25 with an allylic acetate in the presence of a suitable catalyst such as palladium tetrakis(triphenylphosphine) affords compounds of formula 74. Deprotection of the nitrogen affords compounds of formula 75, see Tetrahedron (50) p. 515, 1994 for a detailed discussion. 
Treatment of a ketodiester of formula 76 with an alkyl halide in the presence of a base such as sodium hydride followed by acid-catalyzed hydrolysis and decarboxylation, followed by esterification with methyliodide and a suitable base affords a compound of formula 77. Reaction of a compound of formula 77 with a suitable aldehyde such as formaldehyde and benzylamine affords a compound of formula 78. Reaction of a compound of formula 78 with a hydrazine generates chiral compounds of formula 79. Deprotection of the nitrogen affords compounds of formula 80. 
Treatment of an amine of formula 23 with an acid of formula 11 in an inert solvent such as dichloromethane or DMF by a coupling reagent such as EDC or DCC in the presence of HOBT affords compounds of formula 89. Reaction of compounds of formula 89 with a hydrazine generates compounds of formula 6. Deprotection of the nitrogen affords compounds of formula 7. 
Treatment of a hydroxyacetoacetate ester of formula 90 with an alkyl halide in the presence of a suitable base such as sodium hydride affords compounds of formula 91. Reaction of 91 with a hydrazine generates compounds of formula 92. O-Alkylation of the carbonyl oxygen of 92 affords 93 which is converted to the halide 94. Displacement of the halide X by cyanide ion affords the nitrile 95. Reduction of 95 gives the primary amine 96 which is deprotected and cyclized in the presence of formaldehyde to afford 28. 
Treatment of a beta-keto-protected aminovalerate such as 97 with an alkyl halide in the presence of a suitable base such as sodium hydride affords compounds of formula 98. Reaction of compounds of formula 98 with a hydrazine generates compounds of formula 99. Deprotection of compounds of formula 99 affords primary amines of formula 100. Cyclization of compounds of formula 100 in the presence of formaldehyde affords compounds of formula 28. 
Treatment of the amine of formula 23a with an acid such as 1 in the presence of EDC and HOAT in a suitable solvent provides keto-esters of formula 23b The keto-ester 23b can be treated with a salt of hydrazine in the presence of sodium acetate in refluxing ethanol to give hydrazines of formula 23c. Deprotection under suitable conditions gives amines of formula 4. Coupling of intermediates of formula 4 to amino acids of formula 5 can be effected as described above to give intermediates of formula 6. Deprotection of amine 6 affords compounds of formula 7.
The following examples are provided for the purpose of further illustration only and are not intended to be limitations on the disclosed invention.
Amicon silica 30 xcexcM, 60 xc3x85 pore size, was used for column chromatography. Melting points were taken on a Buchi 510 apparatus and are uncorrected. Proton and carbon NMR spectra were recorded on a Varian XL-300, Bruker AG300, Varian Unity 400 or Bruker AC-250 at 25xc2x0 C. Chemical shifts are expressed in parts per million down field from trimethylsilane. Particle beam mass spectra were obtained on a Hewlett-Packard 5989A spectrometer using ammonia as the source of chemical ionization. For initial sample dissolution, chloroform or methanol was employed. Liquid secondary ion mass spectra (LSIMS) were obtained on a Kratos Concept-1S high resolution spectrometer using cesium ion bombardment on a sample dissolved in a 1:5 mixture of dithioerythritol and dithiothreitol or in a thioglycerol matrix. For initial sample dissolution chloroform or methanol was employed. Reported data are sums of 3-20 scans calibrated against cesium iodide. TLC analyses were performed using E. Merck Kieselgel 60 F254 silica plates visualized (after elution with the indicated solvent(s)) by staining with 15% ethanolic phosphomolybdic acid and heating on a hot plate.
A 0.2-0.5 M solution of the primary amine (1.0 equivalent) in dichloromethane (or a primary amine hydrochloride and 1.0-1.3 equivalents of triethylamine) is treated sequentially with 1.0-1.2 equivalents of the carboxylic acid coupling partner, 1.5-1.8 equivalents hydroxybenzotriazole hydrate (HOBT) or HOAT and 1.0-1.2 equivalents (stoichiometrically equivalent to the quantity of carboxylic acid) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and the mixture is stirred overnight in an ice bath (the ice bath is allowed to warm, thus the reaction mixture is typically held at about 0-20xc2x0 C. for about 4-6 h and about 20-25xc2x0 C. for the remaining period). The mixture is diluted with ethyl acetate or other solvent as specified, and the resulting mixture washed twice with 1N NaOH, twice with 1N HCl (if the product is not basic), once with brine, dried over Na2SO4, and concentrated giving the crude product which is purified as specified. The carboxylic acid component can be used as the dicyclohexylamine salt in coupling to the primary amine or hydrochloride of the latter; in this case no triethylamine is employed.